Comparative Efficacy and Safety of Standard and Biweekly Trifluridine/Tipiracil Regimen in Patients With Colorectal Cancer.

BACKGROUND/AIM: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC. PATIENTS AND METHODS: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29). RESULTS: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan-Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999). CONCLUSION: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event.

Proton Pump Inhibitors Ameliorate Oxaliplatin-induced Peripheral Neuropathy: Retrospective Analysis of Two Real-world Clinical Databases.

BACKGROUND/AIM: Chemotherapy-induced peripheral neuropathy (CIPN) due to oxaliplatin (L-OHP) is a major clinical problem. Effective and safe preventive strategies for CIPN are urgently needed. Although proton pump inhibitors (PPIs) have various off-target effects, their clinical impact on L-OHP-induced CIPN remains unclear. In the present study, we investigated the effects of PPIs on L-OHP-induced CIPN in patients using two real-world clinical databases. PATIENTS AND METHODS: We retrospectively analyzed the electronic medical records of Osaka University Hospital to examine the effect of PPIs on CIPN development in 217 patients who received XELOX (L-OHP plus capecitabine) therapy for colorectal cancer. In addition, the Japanese Adverse Drug Event Report (JADER) database was used to validate the effects of PPIs on L-OHP-induced CIPN. RESULTS: The incidences of CIPN (grade ≥2) and discontinuation of L-OHP were significantly lower in patients with PPIs than in those without PPIs. Multivariate analysis showed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of grade ≥2 CIPN (odds ratio=0.054, p<0.001). Kaplan-Meier analysis showed that the time to onset of grade ≥2 CIPN was significantly prolonged in patients with PPIs without affecting the therapeutic efficacy of L-OHP (p=0.004). Moreover, JADER database analyses revealed that the reporting odds ratio of any PPI for L-OHP-induced CIPN was 0.485. CONCLUSION: Concomitant PPI use ameliorated L-OHP-induced CIPN in patients with colorectal cancer.

A doxycycline-inducible CYP3A4-Caco-2 cell line as a model for evaluating safety of aflatoxin B1 in the human intestine.

Exposure of humans to aflatoxin B1 (AFB1) via ingestion of contaminated agricultural products is a major concern for human health throughout the world because epoxidized AFB1, biotransformed from AFB1 by hepatic CYP3A4, is strongly hepatotoxic and hepatocarcinogenic. Intestinal epithelial cells serve as a physical and physiological barrier against xenobiotics via their intercellular tight junction (TJ) seals and the metabolizing enzyme CYP3A4. However, the effect of AFB1 on the intestinal barrier remains unclear. Here, we investigated the influence of AFB1 on these physical and physiological intestinal barriers by means of an in vitro human intestinal model utilizing doxycycline-inducible CYP3A4-expressing Caco-2 cells, in which CYP3A4 activity is comparable to that in the adult human intestine. Cellular toxicity of AFB1 in induced Caco-2 cells (i.e., cells in which expression of CYP3A4 is induced by doxycycline) was approximately 5 times that of uninduced Caco-2 cells. Exposure to 16 µM AFB1 did not decrease the transepithelial electric resistance (TEER; a measure of TJ barrier integrity) in monolayers of uninduced Caco-2 cells to 95.8 % of that in vehicle-treated cells; in contrast, in induced Caco-2 cells, TEER was reduced to 28.8 %. Exposure to 16 µM AFB1 increased paracellular permeation of 4- and 20-kDa dextrans (paracellular permeation markers) through monolayers of induced Caco-2 cells to 5.4 and 5.2 times that through uninduced Caco-2 cells. These results together show that ingested AFB1 can modulate the intestinal barrier, and that inducible CYP3A4-expressing Caco-2 cells are a promising tool for evaluating the safety of food contaminants in the human intestine.

Repositioning of Lansoprazole as a Protective Agent Against Cisplatin-Induced Ototoxicity.

Cisplatin (CDDP) is a well-known chemotherapeutic drug approved for various cancers. However, CDDP accumulates in the inner ear cochlea via organic cation transporter 2 (OCT2) and causes ototoxicity, which is a major clinical limitation. Since lansoprazole (LPZ), a proton pump inhibitor, is known to inhibit OCT2-mediated transport of CDDP, we hypothesized that LPZ might ameliorate CDDP-induced ototoxicity (CIO). To test this hypothesis, we utilized in vivo fluorescence imaging of zebrafish sensory hair cells. The fluorescence signals in hair cells in zebrafish treated with CDDP dose-dependently decreased. Co-treatment with LPZ significantly suppressed the decrease of fluorescence signals in zebrafish treated with CDDP. Knockout of a zebrafish homolog of OCT2 also ameliorated the reduction of fluorescence signals in hair cells in zebrafish treated with CDDP. These in vivo studies suggest that CDDP damages the hair cells of zebrafish through oct2-mediated accumulation and that LPZ protects against CIO, possibly inhibiting the entry of CDDP into the hair cells via oct2. We also evaluated the otoprotective effect of LPZ using a public database containing adverse event reports. The analysis revealed that the incidence rate of CIO was significantly decreased in patients treated with LPZ. We then retrospectively analyzed the medical records of Mie University Hospital to examine the otoprotective effect of LPZ. The incidence rate of ototoxicity was significantly lower in patients co-treated with LPZ compared to those without LPZ. These retrospective findings suggest that LPZ is also protective against CIO in humans. Taken together, co-treatment with LPZ may reduce the risk of CIO.

Concomitant palonosetron ameliorates cisplatin-induced nephrotoxicity, nausea, and vomiting: a retrospective cohort study and pharmacovigilance analysis.

BACKGROUND: Cisplatin (CDDP)-induced nephrotoxicity is the most important complication of CDDP treatment. 5-Hydroxytryptamine type 3 receptor antagonists (5-HT3RAs) are widely used to prevent chemotherapy-induced nausea and vomiting (CINV). However, in patients with the triple antiemetic (neurokinin-1 receptor antagonist, 5-HT3RA, and dexamethasone) therapy, the advantage of palonosetron in comparison with other 5-HT3RAs on CDDP-induced nephrotoxicity and CINV remains unclear. In the present study, we investigated the effect of palonosetron on CDDP-induced nephrotoxicity and CINV in patients with the triple antiemetic therapy by a retrospective cohort study and a pharmacovigilance analysis. METHODS: We retrospectively analyzed the effect of 5-HT3RAs on the development of nephrotoxicity and CINV in 110 patients who received CDDP, fluorouracil, and triple antiemetic therapy for the treatment of esophageal cancer. Moreover, the effect of 5-HT3RAs on CDDP-induced nephrotoxicity was validated in patients with the triple antiemetic therapy using the Japanese Adverse Drug Event Report (JADER) database. RESULTS: In a retrospective study, the incidence of nephrotoxicity (≥ grade 1) in patients receiving palonosetron (18%) was significantly lower than that in patients receiving ramosetron (another 5-HT3RA) (36%, p = 0.044). Moreover, severe nephrotoxicity ≥ grade 3 was observed in one patient treated with ramosetron, whereas hematological toxicity was comparable between the two groups (p = 0.553). Furthermore, the incidence rate of CINV within 120 h following CDDP administration in patients treated with palonosetron (18%) was significantly lower than that in patients receiving ramosetron (39%, p = 0.026). JADER database analyses revealed that the reporting odds ratio of palonosetron for CDDP-induced acute kidney injury was 0.282 (95% confidence interval: 0.169-0.472). CONCLUSIONS: The findings of the present study suggested a greater potential of palonosetron against CDDP-induced nephrotoxicity and CINV than other 5-HT3RAs in patients with the triple antiemetic therapy.

Proton Pump Inhibitors Ameliorate Capecitabine-induced Hand-Foot Syndrome in Patients With Breast Cancer: A Retrospective Study.

BACKGROUND/AIM: Hand-foot syndrome (HFS) is the most common adverse event associated with capecitabine, and its pathogenesis is known to be associated with inflammation. Proton pump inhibitors (PPIs) reportedly exert anti-inflammatory effects; however, the impact of PPIs on capecitabine-induced HFS needs to be clarified in the clinical setting. In the present study, we retrospectively investigated the efficacy and safety of PPIs in patients with breast cancer receiving capecitabine. PATIENTS AND METHODS: We analyzed the effects of PPIs on the development of severe HFS (grade ≥2), progression-free survival (PFS), and overall survival (OS) in 195 patients who received capecitabine chemotherapy for breast cancer. RESULTS: In total, 50 patients (26%) were treated with PPIs, while 145 patients (74%) did not receive PPIs. The incidence of severe HFS was significantly lower in patients who received PPIs (18%) than in patients who did not receive PPIs (43%, p=0.001), and the discontinuation rate of capecitabine therapy due to HFS was also lower in patients receiving PPIs than in those who did not receive PPIs (p=0.003). Multivariate analysis revealed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of severe HFS (odds ratio (OR)=0.265, p=0.003). Meanwhile, no significant difference in median PFS and OS values was observed between patients treated with and without PPIs. CONCLUSION: Concomitant use of PPIs could ameliorate capecitabine-induced HFS in patients with breast cancer.

Cytomegalovirus skin disease in a kidney transplant patient.

A 44-year-old man with a history of renal transplantation presented with right lower abdominal wall swelling, redness and pain. A bacterial abscess was drained, and he was discharged home with oral antibiotics. After failing to improve, he returned to the hospital, where he was briefly treated with intravenous antibiotics and discharged home again. The patient returned 5 days later, reporting worsening right groin swelling that extended into the ipsilateral scrotum. Imaging revealed a persistent fluid collection in the region, and he was taken for surgical debridement. Tissue immunochemistry and histopathological evaluation identified cytomegalovirus infection. Plasma quantitative PCR for cytomegalovirus demonstrated high viraemia. The patient was successfully treated with intravenous ganciclovir, followed by oral valganciclovir, with resolution of the skin changes. Persistent hydrocele with epididymitis on imaging suggests that this process may have been the source of the cutaneous cytomegalovirus infection.

Effect of number of medications and complexity of regimens on medication adherence and blood pressure management in hospitalized patients with hypertension.

INTRODUCTION: Good adherence of antihypertensives is recommended for the accomplishment of hypertension therapy. The number of medications and characteristics contributing to medication regimen complexity, such as dosage forms and dosing frequency, are known to influence medication adherence. However, the effect of medication regimen complexity on the therapeutic efficacy of medicines remains to be clarified. In the present study, we retrospectively investigated the effect of number of medications and medication regimen complexity on medication adherence and therapeutic efficacy in patients with hypertension. METHODS: According to the inclusion and exclusion criteria, 1,057 patients, who were on medications including antihypertensives on admission at the Mie University Hospital between July 2018 and December 2018, were enrolled in this study. Poor blood pressure management was defined if the systolic or diastolic blood pressure were ≥140 mmHg or ≥ 90 mmHg. Medication regimen complexity was quantified using the medication regimen complexity index (MRCI) score. RESULTS: Among 1,057 patients, 164 and 893 patients were categorized into poor and good adherence groups, respectively. The multivariate analyses revealed that age ≥ 71 years and oral MRCI score ≥ 19.5 but not number of oral medications were extracted as risk factors for poor medication adherence. Medication adherence and blood pressure management were poor in the group with oral MRCI score ≥ 19.5, regardless of the age. The rate of readmission was similar. CONCLUSION: Our study is the first to demonstrate that medication regimen complexity rather than number of medications is closely related to medication adherence and blood pressure management. Hence, physicians and/or pharmacists should consider the complexity of medication regimens while modifying them.

Correlation of Coagulation Parameters With Clinical Outcomes During the Coronavirus-19 Surge in New York: Observational Cohort.

IMPORTANCE: COVID-19 has caused a worldwide illness and New York became the epicenter of COVID-19 in the United States from Mid-March to May 2020. OBJECTIVE: To investigate the coagulopathic presentation of COVID and its natural course during the early stages of the COVID-19 surge in New York. To investigate whether hematologic and coagulation parameters can be used to assess illness severity and death. DESIGN: Retrospective case study of positive COVID inpatients between March 20, 2020-March 31, 2020. SETTING: Montefiore Health System main hospital, Moses, a large tertiary care center in the Bronx. PARTICIPANTS: Adult inpatients with positive COVID tests hospitalized at MHS. EXPOSURE FOR OBSERVATIONAL STUDIES: Datasets of participants were queried for demographic (age, sex, socioeconomic status, and self-reported race and/or ethnicity), clinical and laboratory data. MAIN OUTCOME AND MEASURES: Relationship and predictive value of measured parameters to mortality and illness severity. RESULTS: Of the 225 in this case review, 75 died during hospitalization while 150 were discharged home. Only the admission PT, absolute neutrophil count (ANC) and first D-Dimer could significantly differentiate those who were discharged alive and those who died. Logistic regression analysis shows increased odds ratio for mortality by first D-Dimer within 48 hrs. of admission. The optimal cut-point for the initial D-Dimer to predict mortality was found to be 2.1 µg/mL. 15% of discharged patients required readmission and more than a third of readmitted patients died (5% of all initially discharged). CONCLUSION: We describe here a comprehensive assessment of hematologic and coagulation parameters in COVID-19 and examine the relationship of these to mortality. We demonstrate that both initial and maximum D-Dimer values are biomarkers that can be used for survival assessments. Furthermore, D-Dimer may be useful to follow up discharged patients.

Opioid therapy duration before naldemedine treatment is a significant independent risk of diarrhea: a retrospective cohort study.

BACKGROUND: The most common adverse event (AE) associated with opioid analgesics is opioid-induced constipation (OIC). Naldemedine (NAL) is widely used for the treatment of OIC. However, diarrhea has been reported as the most common treatment-emergent AE of NAL, and little is known about the risk factors associated with the development of diarrhea during NAL administration. This study examined the risk factors for NAL-induced diarrhea via a retrospective chart review of hospitalized patients. METHODS: The data of 101 hospitalized adult patients who received NAL for the first time for the treatment of OIC at Mie University Hospital between June 2017 and December 2018 were extracted from electronic medical records. According to the inclusion and exclusion criteria, 70 of the 101 patients were enrolled in this study. Diarrhea was defined as "diarrhea" on the medical record within 2 weeks of NAL administration. Univariate and multivariate analyses were performed to identify risk factors for the development of diarrhea in patients receiving NAL. RESULTS: Twenty-two of the 70 patients enrolled (31%) developed diarrhea within 2 weeks of NAL administration. The median duration (range) of NAL treatment before diarrhea onset was 3 (1-12) days. Patients with diarrhea had a significantly longer duration of opioid therapy before NAL administration than patients without diarrhea (P=0.002). Multivariate logistic regression analysis indicated that the independent risk factors for the development of NAL-induced diarrhea were NAL administration after more than 17 days of opioid therapy (odds ratio [OR]=7.539; P=0.016) and pancreatic cancer (OR=6.217; P=0.025). In fact, the incidence of diarrhea in patients who were administered NAL within a day of opioid therapy was significantly lower than that in patients who were administered NAL after more than 17 days of opioid therapy (13% vs. 54%, P=0.030). CONCLUSIONS: These results suggested that a prolonged duration of opioid therapy prior to NAL initiation is associated with increased incidence of diarrhea.

Using Automated Machine Learning to Predict the Mortality of Patients With COVID-19: Prediction Model Development Study.

BACKGROUND: During a pandemic, it is important for clinicians to stratify patients and decide who receives limited medical resources. Machine learning models have been proposed to accurately predict COVID-19 disease severity. Previous studies have typically tested only one machine learning algorithm and limited performance evaluation to area under the curve analysis. To obtain the best results possible, it may be important to test different machine learning algorithms to find the best prediction model. OBJECTIVE: In this study, we aimed to use automated machine learning (autoML) to train various machine learning algorithms. We selected the model that best predicted patients' chances of surviving a SARS-CoV-2 infection. In addition, we identified which variables (ie, vital signs, biomarkers, comorbidities, etc) were the most influential in generating an accurate model. METHODS: Data were retrospectively collected from all patients who tested positive for COVID-19 at our institution between March 1 and July 3, 2020. We collected 48 variables from each patient within 36 hours before or after the index time (ie, real-time polymerase chain reaction positivity). Patients were followed for 30 days or until death. Patients' data were used to build 20 machine learning models with various algorithms via autoML. The performance of machine learning models was measured by analyzing the area under the precision-recall curve (AUPCR). Subsequently, we established model interpretability via Shapley additive explanation and partial dependence plots to identify and rank variables that drove model predictions. Afterward, we conducted dimensionality reduction to extract the 10 most influential variables. AutoML models were retrained by only using these 10 variables, and the output models were evaluated against the model that used 48 variables. RESULTS: Data from 4313 patients were used to develop the models. The best model that was generated by using autoML and 48 variables was the stacked ensemble model (AUPRC=0.807). The two best independent models were the gradient boost machine and extreme gradient boost models, which had an AUPRC of 0.803 and 0.793, respectively. The deep learning model (AUPRC=0.73) was substantially inferior to the other models. The 10 most influential variables for generating high-performing models were systolic and diastolic blood pressure, age, pulse oximetry level, blood urea nitrogen level, lactate dehydrogenase level, D-dimer level, troponin level, respiratory rate, and Charlson comorbidity score. After the autoML models were retrained with these 10 variables, the stacked ensemble model still had the best performance (AUPRC=0.791). CONCLUSIONS: We used autoML to develop high-performing models that predicted the survival of patients with COVID-19. In addition, we identified important variables that correlated with mortality. This is proof of concept that autoML is an efficient, effective, and informative method for generating machine learning-based clinical decision support tools.

Temporary decrease in tacrolimus clearance in cytochrome P450 3A5 non-expressors early after living donor kidney transplantation: Effect of interleukin 6-induced suppression of the cytochrome P450 3A gene.

Tacrolimus is important for immunosuppression in kidney transplantation. In this historical cohort and in vitro study, we evaluated the changes in tacrolimus pharmacokinetics early after living donor kidney transplantation and the effects of interleukin (IL)-6 on cytochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5) expression. In the historical cohort study, 22 patients who met the inclusion criteria were classified into CYP3A5 expressors and non-expressors (n = 16 and 6, respectively). The blood tacrolimus concentration per dose ratio (C/D) temporarily increased post-kidney transplantation on days 3-4 only in CYP3A5 non-expressors. The effects of IL-6 on CYP3A4 and CYP3A5 expression were also investigated in vitro using HepG2 and Caco-2 cells. IL-6 induced a significant concentration- and time-dependent decrease in CYP3A4 and CYP3A5 expression in both cells. The mean CYP3A4 expression level at 12 hours after IL-6 exposure (% of 0 hour) was 44.0 and 62.6 in HepG2 and Caco-2 cells, respectively, whereas the CYP3A5 expression level was 30.7 and 52.4, respectively. We hypothesize that CYP3A5 non-expressors might exhibit a temporary decrease in the oral clearance of tacrolimus via an increase in serum IL-6 concentrations early after kidney transplantation. These results may help develop strategies to improve kidney transplant outcome.

Anticoagulation in COVID-19: Effect of Enoxaparin, Heparin, and Apixaban on Mortality.

BACKGROUND: Mortality in coronavirus disease of 2019 (COVID-19) is associated with increases in prothrombotic parameters, particularly D-dimer levels. Anticoagulation has been proposed as therapy to decrease mortality, often adjusted for illness severity. OBJECTIVE: We wanted to investigate whether anticoagulation improves survival in COVID-19 and if this improvement in survival is associated with disease severity. METHODS: This is a cohort study simulating an intention-to-treat clinical trial, by analyzing the effect on mortality of anticoagulation therapy chosen in the first 48 hours of hospitalization. We analyzed 3,625 COVID-19+ inpatients, controlling for age, gender, glomerular filtration rate, oxygen saturation, ventilation requirement, intensive care unit admission, and time period, all determined during the first 48 hours. RESULTS: Adjusted logistic regression analyses demonstrated a significant decrease in mortality with prophylactic use of apixaban (odds ratio [OR] 0.46, p = 0.001) and enoxaparin (OR = 0.49, p = 0.001). Therapeutic apixaban was also associated with decreased mortality (OR 0.57, p = 0.006) but was not more beneficial than prophylactic use when analyzed over the entire cohort or within D-dimer stratified categories. Higher D-dimer levels were associated with increased mortality (p < 0.0001). When adjusted for these same comorbidities within D-dimer strata, patients with D-dimer levels < 1 µg/mL did not appear to benefit from anticoagulation while patients with D-dimer levels > 10 µg/mL derived the most benefit. There was no increase in transfusion requirement with any of the anticoagulants used. CONCLUSION: We conclude that COVID-19+ patients with moderate or severe illness benefit from anticoagulation and that apixaban has similar efficacy to enoxaparin in decreasing mortality in this disease.

Idarubicin, an Anthracycline, Induces Oxidative DNA Damage in the Presence of Copper (II).

BACKGROUND/AIM: The aim of the present study was to investigate whether idarubicin (IDR) induces oxidative DNA damage in the presence of copper (II). MATERIALS AND METHODS: DNA damage was evaluated by pBR322 plasmid DNA cleavage. The formation of oxidative stress markers [O2 •- and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] was analysed. RESULTS: IDR induced DNA damage and O2 •- and 8-OHdG generation in the presence of copper (II). CONCLUSION: IDR induced oxidative DNA damage in the presence of copper (II). Since it has been reported that the concentration of copper in the serum of cancer patients is higher than that in healthy groups, IDR-induced oxidative DNA damage in the presence of copper (II) may play an important role in anticancer therapeutic strategies.

Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats.

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.

Maternal administration of tadalafil improves fetal ventricular systolic function in a Hey2 knockout mouse model of fetal heart failure.

BACKGROUND: There is no established transplacental treatment for heart failure (HF) in utero, and no animal models or experimental systems of fetal HF have been established. This study aimed to investigate the effect of maternal tadalafil administration on fetal cardiovascular function and uteroplacental circulation in a murine model of fetal HF. METHODS AND RESULTS: We first used an ultra-high-frequency ultrasound imaging system in utero and demonstrated that Hey2-/- embryos had worsening right ventricular hypoplasia and marked left ventricular (LV) dilatation as gestation progressed. In both ventricles, fractional shortening (FS) and the E/A ratio were significantly lower in Hey2-/- embryos than in wild-type embryos, indicating that the embryos can be used as a murine model of fetal HF. Subsequently, we evaluated the effect of tadalafil treatment (0.04 or 0.08 mg/ml; T0.04 or T0.08 groups, respectively) on fetoplacental circulation in Hey2-/- embryos. LV FS was significantly higher in the T0.04 group than in control (P < 0.01), whereas LV dilation, mitral E/A ratio, and umbilical artery resistance index were not significantly different among all groups. The thinness of the LV compacted layer did not differ between the T0.04 and vehicle-treated Hey2-/- embryos. CONCLUSIONS: A phenotype comprising marked dilatation and reduced FS of the left ventricles was identified in Hey2-/- embryos, suggesting these embryos as a murine model of fetal HF. In addition, maternal administration of tadalafil improved LV systolic function without altering LV morphological abnormalities in Hey2-/- embryos. Our findings suggest that tadalafil is a potential agent to treat impaired fetal ventricular systolic function.

An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity.

Cisplatin is widely used to treat various types of cancers, but it is often limited by nephrotoxicity. Here, we employed an integrated in silico and in vivo approach to identify potential treatments for cisplatin-induced nephrotoxicity (CIN). Using publicly available mouse kidney and human kidney organoid transcriptome datasets, we first identified a 208-gene expression signature for CIN and then used the bioinformatics database Cmap and Lincs Unified Environment (CLUE) to identify drugs expected to counter the expression signature for CIN. We also searched the adverse event database, Food and Drug Administration. Adverse Event Reporting System (FAERS), to identify drugs that reduce the reporting odds ratio of developing cisplatin-induced acute kidney injury. Palonosetron, a serotonin type 3 receptor (5-hydroxytryptamine receptor 3 (5-HT3R)) antagonist, was identified by both CLUE and FAERS analyses. Notably, clinical data from 103 patients treated with cisplatin for head and neck cancer revealed that palonosetron was superior to ramosetron in suppressing cisplatin-induced increases in serum creatinine and blood urea nitrogen levels. Moreover, palonosetron significantly increased the survival rate of zebrafish exposed to cisplatin but not to other 5-HT3R antagonists. These results not only suggest that palonosetron can suppress CIN but also support the use of in silico and in vivo approaches in drug repositioning studies.

Maternal Blood Concentration of Tadalafil and Uterine Blood Flow in Pregnancy.

: Background and Objectives: Tadalafil for treatment of fetal growth restriction (FGR) or preeclampsia is given once a day orally. The drug kinetics of tadalafil were investigated to determine the ideal dosage to promote uterine blood flow. Materials and Methods: We recruited five pregnant women with FGR or preeclampsia before administration of tadalafil, all of which were administered tadalafil (20 mg/day, once-daily dosing). The blood concentration of tadalafil was measured 1, 2, 4, 6, 8, and 24 h after administration, and uterine blood flow was measured before tadalafil administration and 2-4 and 20-24 h after. We then analyzed the correlation between tadalafil blood concentration and uterine artery blood flow. Results: The blood concentration of tadalafil correlated with uterine artery blood flow in pregnant women. The blood concentration of tadalafil and uterine artery blood flow decreased 5 h after administration of tadalafil. Conclusions: The blood concentration of tadalafil and uterine artery blood flow fluctuate in parallel, the latter was decreased by reduced blood concentration. Thus, a study of tadalafil administered twice a day in pregnant women will be needed to stabilize uterine artery blood flow.

Oxidative DNA Damage and Apoptosis Induced by Aclarubicin, an Anthracycline: Role of Hydrogen Peroxide and Copper.

BACKGROUND/AIM: This study aimed to investigate aclarubicin (ACR)-induced oxidative DNA damage and apoptosis. MATERIALS AND METHODS: ACR-induced apoptosis was analyzed using HL-60 leukemia cells and HP100 cells, hydrogen peroxide (H2O2)-resistant cells derived from HL-60 cells. ACR-induced DNA damage was analyzed using plasmid DNA. RESULTS: HL-60 cells were more sensitive to ACR than HP100 cells. In HP100 cells, DNA ladder formation and caspase-3/7 activity induced by ACR were suppressed or delayed in comparison to those in HL-60 cells. ACR-induced DNA damage occurred in the presence of Cu(II), and scavenger experiments showed that the reactive species causing DNA damage appeared to be generated from H2O2 and Cu(I). Moreover, we detected intracellular Cu(I) induced by ACR in HL-60 cells, using CopperGREEN™, a fluorescent probe for detection of Cu(I) ion specifically. CONCLUSION: ACR-induced DNA damage and apoptosis can be accounted for by the involvement of H2O2 and Cu(I).

Risk factors for the development of hypermagnesemia in patients prescribed magnesium oxide: a retrospective cohort study.

BACKGROUND: Magnesium oxide (MgO), an antacid and laxative, is widely used in Japan to treat constipation and peptic ulcers. Because serum Magnesium (Mg) levels are elevated in elderly and/or patients with renal failure, its periodic monitoring is recommended for patients prescribed MgO, in order to prevent MgO-induced hypermagnesemia. However, there is little information regarding the factors contributing to the development of MgO-induced hypermagnesemia. In the present study, we retrospectively investigated the risk factors of hypermagnesemia in patients prescribed MgO. METHODS: Data of 3258 patients hospitalized in Mie University Hospital between October 2015 and September 2017, who were prescribed MgO tablets, were extracted from the electronic medical records. According to the inclusion and exclusion criteria, 320 of the 3258 patients were enrolled in this study. Hypermagnesemia was defined as serum Mg levels ≥2.5 mg/dL (by the Common Terminology Criteria for Adverse Events version 4.0). Uni- and multivariate analyses were performed to identify risk factors for the development of hypermagnesemia in patients prescribed MgO using the following variables: age, estimated glomerular filtration rate, blood urea nitrogen levels, MgO dose, duration of MgO administration, and co-administrated proton pump inhibitors, H2 blocker (famotidine), vitamin D3 drugs, and diuretics. RESULTS: Seventy-five patients out of 320 (23%) developed grade 1 and grade 3 hypermagnesemia, with the occurrence of grade 1 and grade 3 in 62 (19%) and 13 (4%) patients, respectively. Multivariate logistic regression analyses indicated 4 independent risk factors for hypermagnesemia comprising estimated glomerular filtration rate ≤ 55.4 mL/min (odds ratio (OR): 3.105, P = 0.001), blood urea nitrogen ≥22.4 mg/dL (OR: 3.490, P < 0.001), MgO dose ≥1650 mg/day (OR: 1.914, P = 0.039), and duration of MgO administration ≥36 days (OR: 2.198, P = 0.012). The occurrence rate of hypermagnesemia was elevated in accordance with these risk factors. CONCLUSIONS: These results suggest that a periodic monitoring of serum Mg levels is strongly recommended in MgO prescribed patients, especially in those with multiple risk factors for hypermagnesemia. The present findings provide useful information for the safe management of MgO therapy.