Do calcineurin inhibitors influence the serum concentrations of mizoribine?

Background: Mizoribine (MZR) is an antimetabolite that inhibits inosine-monophosphate dehydrogenase and has been used for preventing rejection in renal transplantation. However, the effect of calcineurin inhibitors (CNIs) on the pharmacokinetics of MZR has not been shown. This study was performed to show the influence of CNIs (tacrolimus [Tac] or cyclosporine [CyA]) on the serum concentration of MZR.Methods: Thirty-four living-donor renal transplant recipients administered a four-drug immunosuppressive therapy regimen (steroid, CNIs, basiliximab and MZR 6 mg/kg/day) were investigated. 20 recipients were treated with Tac and 14 were with CyA. Serum concentrations of MZR were obtained retrospectively at 464 points and at 243 points for each. Population pharmacokinetic (PPK) analysis was used to make pharmacokinetic models of serum MZR. After statistically evaluating the correlation of the pharmacokinetic models with the actual data, areas under the curves (AUCs) of each CNI were also estimated in these models and statistically evaluated.Results: The mean values of the PPK parameters (absorption lag time, absorption rate constant [Ka], apparent volume of distribution [V/F] and oral clearance of MZR [CLMZR/F]) were 0.600 hr and 0.643 hr, 1.14/hr and 0.911/hr, 0.732×body weight (WT) (L) and 0.784×WT (L), and 1.64×creatinine clearance (CLcr) (L/hr) and 1.81×CLcr (L/hr), respectively. Moreover, the serum concentrations of MZR at all-time points were estimated with these parameters. The correlation coefficients between the individual actual and estimated serum concentrations of MZR in the Tac group and the CyA group were 0.988 and 0.992, respectively. The average value of the AUCs of MZR corrected by the CLcr in the Tac group, and the CyA group were 0.61±0.21 and 0.55±0.19 (average value±standard deviation) for each (p=0.19).Conclusion: These findings suggest the pharmacokinetics of MZR were well-described by 1-compartment model with first-order absorption. Moreover, concomitant use of CNIs, e.g., Tac and CyA, may have no significant influence on the pharmacokinetics of MZR

National survey of the association of depressive symptoms with the number of off duty and on-call, and sleep hours among physicians working in Japanese hospitals: a cross sectional study

<p>Abstract</p> <p>Background</p> <p>Physicians' mental health may be adversely affected by the number of days of work and time spent on-call, and improved by sleep and days-off. The aim of this study was to determine the associations of depressive symptoms with taking days of off duty, hours of sleep, and the number of days of on-call and overnight work among physicians working in Japanese hospitals.</p> <p>Methods</p> <p>A cross-sectional study as a national survey was conducted by mail. The study population was 10,000 randomly selected physicians working in hospitals who were also members of the Japan Medical Association (response rate 40.5%). Self-reported anonymous questionnaire was sent to assess the number of days off-duty, overnight work, and on-calls, and the average number of sleep hours on days not working overnight in the previous one month. Depressive state was determined by the Japanese version of the Quick Inventory of Depressive Symptomatology. Logistic regression analysis was used to explore the associations between depressive symptoms and the studied variables.</p> <p>Results</p> <p>Among the respondents, 8.3% of men and 10.5% of women were determined to be depressed. For both men and women, depressive state was associated with having no off-duty days and averaging less than 5 hours of sleep on days not doing overnight work. Depressive state was positively associated with being on-call more than 5 days per month for men, and more than 8 days per month for women, and was negatively associated with being off-duty more than 8 days per month for men.</p> <p>Conclusion</p> <p>Some physicians need some support to maintain their mental health. Physicians who do not take enough days-off, who reduced sleep hours, and who have certain number of days on-calls may develop depressive symptoms.</p

Cores and pH-dependent Dynamics of Ferredoxin-NADP+ Reductase Revealed by Hydrogen/Deuterium Exchange

This research was originally published in the Journal of Biological Chemistry. Young-Ho Lee, Kosuke Tamura, Masahiro Maeda, Masaru Hoshino, Kazumasa Sakurai, Satoshi Takahashi, Takahisa Ikegami, Toshiharu Hase, and Yuji Goto. Cores and pH-dependent Dynamics of Ferredoxin-NADP+ Reductase Revealed by Hydrogen/Deuterium Exchange. J. Biol. Chem. 2007; 282, 5959-5967. © the American Society for Biochemistry and Molecular Biolog

Cholecalciferol Supplementation Attenuates Bone Loss in Incident Kidney Transplant Recipients: A Prespecified Secondary Endpoint Analysis of a Randomized Controlled Trial

Vitamin D deficiency, persistent hyperparathyroidism, and bone loss are common after kidney transplantation (KTx). However, limited evidence exists regarding the effects of cholecalciferol supplementation on parathyroid hormone (PTH) and bone loss after KTx. In this prespecified secondary endpoint analysis of a randomized controlled trial, we evaluated changes in PTH, bone metabolic markers, and bone mineral density (BMD). At 1 month post-transplant, we randomized 193 patients to an 11-month intervention with cholecalciferol (4000 IU/d) or placebo. The median baseline 25-hydroxyvitamin D (25[OH]D) level was 10 ng/mL and 44% of participants had osteopenia or osteoporosis. At the end of the study, the median 25(OH)D level was increased to 40 ng/mL in the cholecalciferol group and substantially unchanged in the placebo group. Compared with placebo, cholecalciferol significantly reduced whole PTH concentrations (between-group difference of −15%; 95% confidence interval [CI] −25 to −3), with greater treatment effects in subgroups with lower 25(OH)D, lower serum calcium, or higher estimated glomerular filtration rate (pint < 0.05). The percent change in lumbar spine (LS) BMD from before KTx to 12 months post-transplant was −0.2% (95% CI −1.4 to 0.9) in the cholecalciferol group and −1.9% (95% CI −3.0 to −0.8) in the placebo group, with a significant between-group difference (1.7%; 95% CI 0.1 to 3.3). The beneficial effect of cholecalciferol on LS BMD was prominent in patients with low bone mass pint < 0.05). Changes in serum calcium, phosphate, bone metabolic markers, and BMD at the distal radius were not different between groups. In mediation analyses, change in whole PTH levels explained 39% of treatment effects on BMD change. In conclusion, 4000 IU/d cholecalciferol significantly reduced PTH levels and attenuated LS BMD loss after KTx. This regimen has the potential to eliminate vitamin D deficiency and provides beneficial effects on bone health even under glucocorticoid treatment. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).Tsujita M., Doi Y., Obi Y., et al. Cholecalciferol Supplementation Attenuates Bone Loss in Incident Kidney Transplant Recipients: A Prespecified Secondary Endpoint Analysis of a Randomized Controlled Trial. Journal of Bone and Mineral Research 37, 303 (2022); https://doi.org/10.1002/jbmr.4469

Treatment for secondary hyperparathyroidism focusing on parathyroidectomy

Secondary hyperparathyroidism (SHPT) is a major problem for patients with chronic kidney disease and can cause many complications, including osteodystrophy, fractures, and cardiovascular diseases. Treatment for SHPT has changed radically with the advent of calcimimetics; however, parathyroidectomy (PTx) remains one of the most important treatments. For successful PTx, removing all parathyroid glands (PTGs) without complications is essential to prevent persistent or recurrent SHPT. Preoperative imaging studies for the localization of PTGs, such as ultrasonography, computed tomography, and 99mTc-Sestamibi scintigraphy, and intraoperative evaluation methods to confirm the removal of all PTGs, including, intraoperative intact parathyroid hormone monitoring and frozen section diagnosis, are useful. Functional and anatomical preservation of the recurrent laryngeal nerves can be confirmed via intraoperative nerve monitoring. Total or subtotal PTx with or without transcervical thymectomy and autotransplantation can also be performed. Appropriate operative methods for PTx should be selected according to the patients’ need for kidney transplantation. In the case of persistent or recurrent SHPT after the initial PTx, localization of the causative PTGs with autotransplantation is challenging as causative PTGs can exist in the neck, mediastinum, or autotransplanted areas. Additionally, the efficacy and cost-effectiveness of calcimimetics and PTx are increasingly being discussed. In this review, medical and surgical treatments for SHPT are described

The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study

It is unknown whether cholecalciferol supplementation improves allograft outcomes in kidney transplant recipients (KTRs). We conducted a single-center randomized, double-blind, placebo-controlled trial of daily 4000 IU cholecalciferol supplementation in KTRs at 1-month posttransplant. The primary endpoint was the change in eGFR from baseline to 12-month posttransplant. Secondary endpoints included severity of interstitial fibrosis and tubular atrophy (IFTA) at 12-month posttransplant and changes in urinary biomarkers. Of 193 randomized patients, 180 participants completed the study. Changes in eGFR were 1.2 mL/min/1.73 m2 (95% CI; −0.7 to 3.1) in the cholecalciferol group and 1.8 mL/min/1.73 m2 (95% CI, −0.02 to 3.7) in the placebo group, with no significant between-group difference (−0.7 mL/min/1.73 m2 [95% CI; −3.3 to 2.0], p = 0.63). Subgroup analyses showed detrimental effects of cholecalciferol in patients with eGFR <45 mL/min/1.73 m2 (Pinteraction <0.05, between-group difference; −4.3 mL/min/1.73 m2 [95% CI; −7.3 to −1.3]). The degree of IFTA, changes in urine albumin-to-creatinine ratio, or adverse events including hypercalcemia and infections requiring hospitalization did not differ between groups. In conclusion, cholecalciferol supplementation did not affect eGFR change compared to placebo among incident KTRs. These findings do not support cholecalciferol supplementation for improving allograft function in incident KTRs. Clinical trial registry: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as UMIN000020597 (please refer to the links below). UMIN-CTR: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000023776.Doi Y., Tsujita M., Hamano T., et al. The effect of cholecalciferol supplementation on allograft function in incident kidney transplant recipients: A randomized controlled study. American Journal of Transplantation 21, 3043 (2021); https://doi.org/10.1111/ajt.16530

CA9 and PRELID2; hypoxia-responsive potential therapeutic targets for pancreatic ductal adenocarcinoma as per bioinformatics analyses

A strong hypoxic environment has been observed in pancreatic ductal adenocarcinoma (PDAC) cells, which contributes to drug resistance, tumor progression, and metastasis. Therefore, we performed bioinformatics analyses to investigate potential targets for the treatment of PDAC. To identify potential genes as effective PDAC treatment targets, we selected all genes whose expression level was related to worse overall survival (OS) in The Cancer Genome Atlas (TCGA) database and selected only the genes that matched with the genes upregulated due to hypoxia in pancreatic cancer cells in the dataset obtained from the Gene Expression Omnibus (GEO) database. Although the extracted 107 hypoxia-responsive genes included the genes that were slightly enriched in angiogenic factors, TCGA data analysis revealed that the expression level of endothelial cell (EC) markers did not affect OS. Finally, we selected CA9 and PRELID2 as potential targets for PDAC treatment and elucidated that a CA9 inhibitor, U-104, suppressed pancreatic cancer cell growth more effectively than 5-fluorouracil (5-FU) and PRELID2 siRNA treatment suppressed the cell growth stronger than CA9 siRNA treatment. Thus, we elucidated that specific inhibition of PRELID2 as well as CA9, extracted via exhaustive bioinformatic analyses of clinical datasets, could be a more effective strategy for PDAC treatment

Three-dimensional Structure of Nylon Hydrolase and Mechanism of Nylon-6 Hydrolysis

This research was originally published in the Journal of Biological Chemistry. Seiji Negoro, Naoki Shibata, Yusuke Tanaka, Kengo Yasuhira, Hiroshi Shibata, Haruka Hashimoto, Young-Ho Lee, Shohei Oshima, Ryuji Santa, Shohei Oshima, Kozo Mochiji, Yuji Goto, Takahisa Ikegami, Keisuke Nagai, Dai-ichiro Kato, Masahiro Takeo and Yoshiki Higuchi. Three-dimensional Structure of Nylon Hydrolase and Mechanism of Nylon-6 Hydrolysis. J. Biol. Chem. 2012; 287, 5079-5090. © the American Society for Biochemistry and Molecular Biolog

Pre-Transplant Calcimimetic Use and Dose Information Improves the Accuracy of Prediction of Tertiary Hyperparathyroidism after Kidney Transplantation: A Retrospective Cohort Study

Tertiary hyperparathyroidism (THPT) is characterized by elevated parathyroid hormone and serum calcium levels after kidney transplantation (KTx). To ascertain whether pre-transplant calcimimetic use and dose information would improve THPT prediction accuracy, this retrospective cohort study evaluated patients who underwent KTx between 2010 and 2022. The primary outcome was the development of clinically relevant THPT. Logistic regression analysis was used to evaluate pre-transplant calcimimetic use as a determinant of THPT development. Participants were categorized into four groups according to calcimimetic dose, developing two THPT prediction models (with or without calcimimetic information). Continuous net reclassification improvement (CNRI) and integrated discrimination improvement (IDI) were calculated to assess ability to reclassify the degree of THPT risk by adding pre-transplant calcimimetic information. Of the 554 patients, 87 (15.7%) developed THPT, whereas 139 (25.1%) received pre-transplant calcimimetic treatment. Multivariate logistic regression analysis revealed that pre-transplant calcimimetic use was significantly associated with THPT development. Pre-transplant calcimimetic information significantly improved the predicted probability accuracy of THPT (CNRI and IDI were 0.91 [p &lt; 0.001], and 0.09 [p &lt; 0.001], respectively). The THPT prediction model including pre-transplant calcimimetic information as a predictive factor can contribute to the prevention and early treatment of THPT in the era of calcimimetics