Prenatal and childhood exposure to bisphenols and bone mineral density in 7-year-old children from the Odense Child Cohort.

BACKGROUND: Bisphenol A (BPA) is a well-known endocrine disrupter used in several consumer products. Restricted use of BPA has led to increased use of bisphenol F (BPF) and bisphenol S (BPS). While previous studies found no associations between prenatal BPA and BPF exposure and bone mineral density (BMD), two recent cohort studies found that prenatal BPS exposure was negatively associated with bone mineral density in the offspring. AIM: To determine possible associations between maternal and child urinary bisphenol concentrations, BMD and bone mineral content (BMC) in 7-year-old healthy children. METHODS: Pregnant women were recruited in 2010-2012 to participate in the Odense Child Cohort (OCC), Denmark. Maternal urine samples were collected in gestational week 28 and urinary BPA concentration was measured by isotope diluted LC-MS/MS. The children delivered a urine sample at age 7 years in which BPA, BPF and BPS were measured by an extended LS-MS/MS method based on the original method. At age 7 years DXA scans were performed and BMC and Z-score for BMD calculated. Associations between osmolality adjusted urinary maternal BPA and child BPA, BPF and BPS concentrations and BMC and BMD Z-score were examined by multiple linear regression analysis adjusted for potential confounders. Additionally, a combined effect of the bisphenols were evaluated by including the sum of child urinary BPA, BPF and BPS concentrations in the statistical analyses. RESULTS: A total of 546 mothers and 453 children aged 7 years participated. BPA was detected in 84% and 96% of the maternal and child urine samples, respectively. We found no significant association between maternal urinary BPA concentration during pregnancy and BMC and BMD Z-score in 7-year-old children. In addition, no association between current bisphenol exposure in tertiles and bone density was found, interestingly, current BPA and summed bisphenol exposure in the highest 10% was associated with lower BMD Z-score at age 7-years, statistically significant for boys. CONCLUSION: In these low exposed children we found no association between prenatal or current bisphenol exposure in tertiles and BMD in healthy children, however, the highest 10% exposed children had lower BMD, significant for boys, suggesting a negative impact with high bisphenol exposure. The short half-lives of bisphenols and the cross-sectional nature of the child exposure prompt more longitudinal studies to further clarify this topic.

Single-dose nonsteroidal anti-inflammatory drugs in horses have no impact on concentrations of cytokines or growth factors in autologous protein solution and platelet-rich plasma.

OBJECTIVE: To determine the effects of a single dose of the NSAIDs phenylbutazone, firocoxib, flunixin meglumine, and ketoprofen on concentrations of growth factors and cytokines in autologous protein solution (APS) and platelet-rich plasma (PRP). ANIMALS: 6 adult university-owned horses. METHODS: For the first phase, 6 horses were randomized to receive ketoprofen (1,000 mg) or flunixin meglumine (500 mg) IV. Blood was obtained and processed for APS (Pro-Stride) and PRP (Restigen) before and 6 hours after administration of NSAIDs. Horses underwent a 2-week washout period, after which the protocol was repeated using a crossover design. For the second phase, following at least a 2-week washout period, the study protocol was repeated with phenylbutazone (1 g) or firocoxib (57 mg) administered orally. Plasma was collected 6 hours after administration for evaluation of drug concentrations, and APS and PRP were analyzed for concentrations of drug, platelets, leukocytes, and several growth factors and cytokines (PDGF, fibroblast growth factor, TGF-ß1, IL-1ß, IL-10, IL-6, IL-8, and tumor necrosis factor-α) before and 6 hours after administration of NSAIDs using immunoassays. RESULTS: There were no significant differences in concentrations of cytokines or growth factors before or after administration of any NSAID. There were significant differences in concentrations of leukocytes and platelets based on both product and time. NSAID concentrations in plasma were not significantly different from concentrations in APS and PRP. CLINICAL RELEVANCE: These results help guide clinicians on the appropriate use of these NSAIDs in conjunction with the processing of APS and PRP, which is unlikely to significantly alter the final product after single-dose administration.

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Left Ventricular Hypertrophy (ESES-LVH) Study: A Multicenter, Open-Label, Prospective, Interventional Study.

INTRODUCTION: In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB). METHODS: This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety. RESULTS: In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified. CONCLUSION: Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071190043).

Selective COX-2 inhibitors do not increase gastrointestinal reactions after colorectal cancer surgery: a systematic review and meta-analysis.

BACKGROUND: The effectiveness of selective COX-2 inhibitors in preventing colorectal cancer recurrence has been demonstrated, however it is unknown how safe and successful they will be over the long term. As a result, we looked at the efficacy, safety, and consequences of adding COX-2 inhibitors to the treatment plan afterward. METHODS: In patients with advanced colorectal cancer, we compared the efficacy of celecoxib at two different doses (200 mg twice day and 400 mg twice daily) with placebo. To evaluate the impacts of post-treatment, several datasets from inception to June 2022 were searched. Response rate, illness control rate, and 3-year survival were the main results. And evaluated several safety outcomes, particularly those that were susceptible to adverse events. RESULTS: The study comprised a total of 9 randomized controlled trials (3206 participants). Celecoxib and rofecoxib doidn't significantly improved the 1-3 year remission rate (OR, 1.57 [95% CI: 0.95-2.57]) and disease control rate (OR, 1.08 [95% CI: 0.99-1.17]). Subgroup analysis of different doses showed that 400 mg of celecoxib significantly improved the response rate (OR, 2.82 [95%CI: 1.20-6.61]). 200 mg celecoxib was not significant (OR, 1.28 [95% CI: 0.66-2.49]). Rofecoxib also did not fully improve disease response rates. Celecoxib at any dose improved 3-year survival (OR, 1.21 [95% CI: 1.02-1.45]). It is important to note that COX-2 inhibitors did not significantly enhance the likelihood of adverse events including gastrointestinal or cardiovascular side effects at any dose. CONCLUSIONS: For patients with advanced colorectal cancer, a reasonable chemoprevention regimen can include celecoxib 400 mg twice daily.

[Evaluation of the efficiency and safety of the dispersed form of sildenafil (50 mg) in males with erectile dysfunction].

INTRODUCTION: The erectile dysfunction is defined as an inability to achieve or maintain an erection sufficient for sexual intercourse lasting more than 3 months. According to literature, about 90 million men worldwide suffer from erectile dysfunction of different severity. AIM: To evaluate the efficacy and safety of the dispersed form of sildenafil ("Ridzhamp" 50 mg), compared with the standard tablets of sildenafil (50 mg). MATERIALS AND METHODS: The study included 60 men aged 27 to 67 years (average age 40.2 years) with moderate erectile dysfunction (11-15 points according to IIEF-5). In group I (n=30), patients took a dispersible form of the drug sildenafil, 50 mg ("Ridzhamp") 60 minutes before sexual intercourse; in group II (n=30), a standard form of the drug sildenafil was prescribed at a dosage of 50 mg, 60 minutes before sexual intercourse. RESULTS: Positive dynamics according to IIEF-5 score was found in all the study groups. In group I, IIEF-5 score increase by 53.85%, while in group II by 50% (p<0.05). The average onset of erection in group I was 45+/-2.2 min, while in group II it was 51+/-1.9 min. In the main group (group I) one patient (3.33%) complained of persistent headache after taking the drug, and therefore refused the therapy. In the comparison group (group II) one patient (3.33%) reported dyspeptic disorders while taking the drug, 1 patient (3.33%) reported dizziness. All patients in the main group noted the convenience of taking the "Ridzhamp". CONCLUSIONS: Our results indicate the comparable efficiency of the dispersed form of sildenafil (group I) and the standard tablet form of the drug (group II). All patients in the main group (group I) noted a faster onset of erections, as well as the convenience of "Ridzhamp" and the ability to take the drug without water intake.

[Selective cyclooxygenase-2 inhibitor hypersensitivity]. / Hipersensibilidad selectiva a inhibidores de la ciclooxigenasa-2.

BACKGROUND: The cyclooxygenase-2 inhibitors are usually recommended as a safe alternative in patients with multiple hypersensitivity to non-steroidal antiinflammatory drugs. Nevertheless, both immediate and delayed hypersensitivity reactions have been described, and the possibility of cross-reactivity with sulphonamides. CASE REPORT: A 66-year-old patient who, after taking a celecoxib tablet, presented with latency of several hours a skin reaction. Previously, he had presented a minor reaction during treatment with etoricoxib without establishing the correlation at that time. The patient underwent an allergological study by means of skin tests with negative results and an oral challenged test with etoricoxib with positive results. Tolerance to sulfonamides was proven. CONCLUSIONS: We present a singular case of a cross-reactivity skin reaction to etoricoxib and celecoxib, suggesting the need to perform challenge tests to confirm the tolerance or not of each drug before allowing their use. On the contrary, trimethropim/sulfamethoxazole could be safely used in our patients, if needed.

INTRODUCCIÓN: Los inhibidores de la ciclooxigenasa-2 suelen indicarse en pacientes con hipersensibilidad múltiple a los antiinflamatorios no esteroides. Sin embargo, se han descrito reacciones de hipersensibilidad inmediata y retardada, además de posible reactividad cruzada con sulfonamidas. REPORTE DE CASO: Paciente masculino de 66 años, que acudió al servicio de Alergia por una reacción cutánea, luego de haber consumido un comprimido de celecoxib. Previamente, durante el tratamiento con etoricoxib, tuvo una reacción menor, sin establecer la correlación farmacológica. Se realizaron pruebas cutáneas (intraepidérmicas y epicutáneas), con resultados negativos, y un examen de exposición oral controlada con etoricoxib, con resultado positivo. Se comprobó la tolerancia a las sulfamidas. CONCLUSIONES: El caso de reacción cutánea, mediante reactividad cruzada, entre etoricoxib y celecoxib expuesto en este artículo sugiere la necesidad de realizar pruebas de provocación para confirmar la tolerancia de cada fármaco antes de su prescripción. Por el contrario, trimetropim-sulfametoxazol pueden indicarse con seguridad, si fuese necesario.

Clinical Pharmacokinetics and Pharmacodynamics of Esaxerenone, a Novel Mineralocorticoid Receptor Antagonist: A Review.

Esaxerenone is a selective, nonsteroidal, high-affinity mineralocorticoid receptor antagonist recently approved in Japan for the treatment of hypertension. It has high oral biovailability, a large volume of distribution, and is primarly metabolized in liver and excreted in bile. Esaxerenone is an efficient antihypertensive, whether given alone or as add-on therapy. The antihypertensive effect is accompanied by renoprotective action, which is being further investigated in current clinical trials. Due to its relatively long half-life and high affinity for the mineralocorticoid receptor, esaxerenone is administered once daily and in low absolute doses. The safety of esaxerenone is considerable, since hyperkalemia is not frequent and, when it does appear, not sustained. Endocrine adverse events, which frequently occur with steroidal mineralocorticoid receptor antagonists, are extremely rare with esaxerenone. Although the risk of clinically significant drug-drug interactions is not high, esaxerenone treatment should start with low doses, with subsequent titration to achieve the optimal clinical effect, all while monitoring serum potassium and paying attention to concomitant therapy with drugs that may induce or inhibit esaxerenone metabolism. This review article offers comprehensive information about the pharmacodynamics and pharmacokinetics of esaxerenone in humans, which should help clinicians to more precisely tailor esaxerenone dosing regimens to their patients.

Comprehensive analysis based in silico study of alternative bisphenols - Environmental explanation of prostate cancer progression.

Industries have begun to shift their focus on exploring substitute chemicals for BPA due to their concerns about safety and environmental pollution. In recent years, alternative bisphenols, including BPS, BPF, and BPAF have been extensively used as BPA substitutes. Based on previous studies, BPA is considered a risk factor for prostate cancer. This work aims to explore the interactive genes related to alternative bisphenols and prostate cancer using the TCGA, CTD, and GEO databases. After performing the GO and KEGG enrichment analysis, a correlation between alternative bisphenols and prostate cancer was detected using bioinformatics analysis. Among the interactive genes of alternative bisphenols, ferroptosis-related genes revealed strong correlations with prostate cancer. Moreover, the prognostic predictive model, ROC curve, and survival analysis confirmed that ferroptosis-related genes displayed a strong correlation in the prognosis of prostate cancer. We successfully evaluated the relationship between prostate cancer and alternative bisphenols; as a result, a novel approach was proposed to explore the damaging effect of environmental endocrine disruptors.

Bisphenol S leads to cytotoxicity-induced antioxidant responses and oxidative stress in isolated rainbow trout (Oncorhyncus mykiss) hepatocytes.

BACKGROUND: Bisphenol S (BPS) is a chemical compound that is utilized in the plastic industry as an alternative to bisphenol A (BPA). The toxic effects of BPS in fish is less known and limited. Therefore, in the present study, the influence of BPS on rainbow trout (Oncorhyncus mykiss) hepatocytes in vitro was investigated. METHODS AND RESULTS: For this purpose the fish hepatocytes were isolated, and then the cultured cells were treated with increasing concentrations of BPS (0, 15.63, 31.25, 62.50, 125, 250, and 500 µM) for 24 h. The cytotoxic impact of BPS was determined in the culture media using lactate dehydrogenase assay and then, the antioxidant defence indicators were assayed. The results showed that concentration-dependent increases were observed in the percentage of cytotoxicity. The superoxide dismutase activity was reduced, while the catalase and glutathione peroxidase activity increased with all of the BPS concentrations. The glutathione S-transferase (GST) activity significantly increased after a BPS concentration of 31.25 µM or higher, while GST Theta 1-1 activity was decreased by the same concentrations of BPS. The reduced glutathione content significantly decreased with a BPS concentration of 31.25 µM or higher, and the malondialdehyde content increased after BPS concentrations of 125, 250, and 500 µM. CONCLUSIONS: The findings determined herein suggested that BPS causes cytotoxicity in fish hepatocytes and can lead to oxidative stress, resulting hepatotoxic in fish. Thus, the utilization of BPS instead of BPA as safe alternative in industry should be re-evaluated in the future for environmental health.

Effects of Repeated Oral Administration of Esaxerenone on the Pharmacokinetics of Midazolam in Healthy Japanese Males.

BACKGROUND AND OBJECTIVE: Esaxerenone showed the potential to inhibit and induce activity against cytochrome P450 (CYP) 3A in in vitro studies. We investigated whether repeated administration of 5 mg/day esaxerenone for 14 days influences the pharmacokinetics of midazolam, a sensitive CYP3A substrate, in healthy Japanese males. METHODS: This single-centre, open-label, single-sequence study had two administration periods: period 1: single oral dose of 2 mg midazolam (day 0); period 2: repeated oral doses of 5 mg/day esaxerenone for 14 days, with a single oral dose of 2 mg midazolam on day 14. Full pharmacokinetic profiles of midazolam and 1-hydroxymidazolam on days 0 and 14 and safety data were obtained. Primary pharmacokinetic endpoints for midazolam were area under the plasma concentration-time curve (AUC) from zero to time of the last measurable concentration (AUClast), AUC from zero to infinity (AUCinf), and peak plasma concentration (Cmax). RESULTS: The study included 28 male subjects. One subject was withdrawn because of a mild adverse event (increased hepatic enzyme levels) that resolved without intervention. Repeated administration of esaxerenone increased midazolam AUClast, AUCinf, and Cmax by about 1.2-fold (1.201, 1.201, and 1.224, respectively) compared with administration of midazolam alone. However, repeated administration of esaxerenone did not affect the elimination half-life of midazolam (2.86 versus 2.63 h with and without esaxerenone). There were no safety concerns associated with concomitant administration of esaxerenone and midazolam. CONCLUSIONS: Esaxerenone 5 mg/day had no clinically significant effect on midazolam pharmacokinetics and was not associated with any safety issues. Esaxerenone can be concomitantly administered with drugs of CYP3A substrates without dose adjustments. CLINICAL TRIAL REGISTRATION: JapiCTI-152832.

Combination therapy using nitro compounds improves the efficacy of experimental Chagas disease treatment.

Drug combinations have been evaluated for Chagas disease in an attempt to improve efficacy and safety. In this line, the objective of this work is to assess the effects of treatment with nitro drugs combinations using benznidazole (BZ) or nifurtimox (NFX) plus the sulfone metabolite of fexinidazole (fex-SFN) in vitro and in vivo on Trypanosoma cruzi infection. The in vitro interaction of fex-SFN and BZ or NFX against infected H9c2 cells by the Y strain was classified as an additive (0.5⩾ΣFIC<4), suggesting the possibility of a dose reduction in the in vivo T. cruzi infection. Next, the effect of combining suboptimal doses was assessed in an acute model of murine T. cruzi infection. Drug combinations led to a faster suppression of parasitemia than monotherapies. Also, the associations led to higher cure levels than those in the reference treatment BZ 100 mg day−1 (57.1%) (i.e. 83.3% with BZ/fex-SFN and 75% with NFX/fex-SFN). Importantly, toxic effects resulting from the associations were not observed, according to weight gain and hepatic enzyme levels in the serum of experimental animals. Taken together, this study is a starting point to explore the potential effects of nitro drugs combinations in preclinical models of kinetoplastid-related infections.

Comparing effects and action mechanisms of BPA and BPS on HTR-8/SVneo placental cells†.

Bisphenol A (BPA) is one of the most investigated compound as a suspected endocrine disrupting chemical. It has been found at nM concentrations in the maternal serum, cord serum, and amniotic fluid and also permeates placental tissues. Attempts are being made to replace BPA with the analog Bisphenol S (BPS). Also BPS was found in maternal and umbilical cord serum, and urine samples from a large population of pregnant women. A few studies investigated BPA impact on the placentation process, and even less are available for BPS. This work aimed to elucidate and compare the effects of BPA and BPS on physiological functions of HTR-8/SVneo cells, derived from extravillous trophoblast of first-trimester pregnancy. Proliferation and migration ability of trophoblast cells were assessed in vitro after exposure to BPA or BPS (10-13-10-3 M). Further, induction of the inflammatory response by the bisphenols was studied. To provide insight into the molecular pathways implicated in the responses, experiments were carried out in the presence or absence of tamoxifen as estrogen receptors (ERs) blocker, and U0126 as ERK1/2 phosphorylation inhibitor. Data indicate that BPA significantly affects both proliferation and migration of HTR-8/SVneo cells, through ER and ERK1/2 mediated processes. Differently, BPS only acts on proliferation, again through ER and ERK1/2 mediated processes. BPS, but not BPA, induces secretion of interleukins 6 and 8. Such effect is inhibited by blocking ERK1/2 phosphorylation. To the best of our knowledge, these are the first data showing that BPS affects trophoblast functions through ER/MAPK modulation.

Prenatal urinary concentrations of phenols and risk of preterm birth: exploring windows of vulnerability.

OBJECTIVE: To explore windows of vulnerability to prenatal urinary phenol concentrations and preterm birth. DESIGN: Prospective cohort. SETTING: A large fertility center in Boston, Massachusetts. PATIENT(S): A total of 386 mothers who sought fertility treatment and gave birth to a singleton between 2005 and 2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Singleton live birth with gestational age <37 completed weeks. RESULT(S): Compared with women with non-preterm births, urinary bisphenol A (BPA) concentrations were higher across gestation among women with preterm births, particularly during mid-to-late pregnancy and among those with female infants. Second trimester BPA concentrations were associated with preterm birth (Risk Ratio [RR] 1.24; 95%CI: 0.92, 1.69), which was primarily driven by female (RR 1.40; 95%CI: 1.04, 1.89) and not male (RR 0.85; 95%CI 0.50, 1.46) infants. First trimester paraben concentrations were also associated with preterm birth (RR 1.17; 95%CI: 0.94, 1.46) and similarly the association was only observed for female (RR 1.46; 95% CI: 1.10, 1.94) and not male infants (RR 0.94; 95%CIC: 0.72, 1.23). First trimester urinary bisphenol S concentrations showed a suggested risk of preterm birth (RR 1.25; 95%CI: 0.82, 1.89), although the small case numbers precluded sex-specific examination. CONCLUSION(S): We found preliminary evidence of associations between mid-to-late pregnancy BPA and early pregnancy paraben concentrations with preterm birth among those with female infants only. Preterm birth risk may be compound, sex, and window specific. Given the limited sample size of this cohort, results should be confirmed in larger studies, including fertile populations.

Study on the Joint Toxicity of BPZ, BPS, BPC and BPF to Zebrafish.

Bisphenol Z (BPZ), bisphenol S (BPS), bisphenol C (BPC), and bisphenol F (BPF) had been widely used as alternatives to bisphenol A (BPA), but the toxicity data of these bisphenol analogues were very limited. In this study, the joint toxicity of BPZ, BPS, BPC, and BPF to zebrafish (Danio rerio) was investigated. The median half lethal concentrations (LC50) of BPZ, BPS, BPC, and BPF to zebrafish for 96 h were 6.9 × 105 µM, 3.9 × 107 µM, 7.1 × 105 µM, and1.6 × 106 µM, respectively. The joint toxicity effect of BPF-BPC (7.7 × 105-3.4 × 105µM) and BPZ-BPC (3.4 × 105-3.5 × 105µM) with the same toxic ratio showed a synergistic effect, which may be attributed to enzyme inhibition or induction theory. While the toxicity effect of the other two bisphenol analogue combined groups and multi-joint pairs showed an antagonistic effect due to the competition site, other causes need to be further explored. Meanwhile, the expression levels of the estrogen receptor genes (ERα, ERß1) and antioxidant enzyme genes (SOD, CAT, GPX) were analyzed using a quantitative real-time polymerase chain reaction in zebrafish exposure to LC50 of BPZ, BPS, BPC, and BPF collected at 24, 48, 72, and 96 h. Relative expression of CAT, GPX, and ERß1 mRNA declined significantly compared to the blank control, which might be a major cause of oxidant injury of antioxidant systems and the disruption of the endocrine systems in zebrafish.

Inflammatory myofibroblastic tumor: molecular landscape, targeted therapeutics, and remaining challenges.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor of intermediate malignant potential that predominantly affects children, adolescents and young adults. IMT has a predilection for the lung, abdomen, pelvis, and retroperitoneum, however, can affect any part of the body. IMT is typically localized, and multifocal or metastatic disease is uncommon. Complete surgical resection is the treatment of choice when feasible. There is no established standard of care for unresectable and advanced IMT. Approximately half of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, and fusions involving ROS1, PDGFRß, RET and NTRK have also been described. Given the molecular landscape of IMT, management of these tumors has evolved to include tyrosine kinase inhibitors and novel targeted therapeutics. This review highlights the molecular characteristics, evolution of targeted therapies and the remaining challenges in the management of IMT.

A phase I study of the anaplastic lymphoma kinase inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors.

In this phase I, dose-escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c-ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine-based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab-paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC-MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c-MET) and c-Jun N-terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty-one patients were evaluable for dose-limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression-free survival was 4.8 months. Three out of five response-evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c-MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.

Efficacy and safety of esaxerenone (CS-3150) in Japanese patients with type 2 diabetes and macroalbuminuria: a multicenter, single-arm, open-label phase III study.

BACKGROUND: Esaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine). METHODS: We conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and treated with a renin-angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K+) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K+ increase, and change in eGFR from baseline. RESULTS: UACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K+ levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K+ values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was - 8.3 mL/min/1.73 m2 at week 24. CONCLUSIONS: Esaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine. CLINICAL TRIAL REGISTRATION: JapicCTI-173696.

Factors Associated with Exposure to Dietary Bisphenols in Adolescents.

Obesogenic endocrine-disrupting chemicals, such as bisphenol A (BPA) and its analogue bisphenol S (BPS), seem to play an important role in the development of obesity, although contradictory results have been reported. The aim of the present study was to conduct a gender analysis of the factors associated with exposure to dietary bisphenols in 585 Spanish adolescents. Dietary BPA and BPS exposure was assessed using a food frequency questionnaire. Foods and macronutrients accounting for more than 95% of energy intake were selected for analysis. Stepwise regression was used to estimate the foods that most contributed to dietary bisphenol exposure in the sample. Gender-related factors associated with greater dietary bisphenol exposure were evaluated using multivariate logistic regression models. Canned tuna was the main dietary source of BPA and BPS in both adolescent boys and girls. Overweight/obese girls showed a higher risk of high dietary exposure to BPA (odds ratio (OR): 3.38, 95% confidence interval (CI): 1.25-9.07) and total bisphenols (OR: 2.81, 95% CI: 1.03-7.67) in comparison with girls with a BMI lower than 25 kg/m2. Present results indicate a positive association of dietary exposure to both total bisphenols and BPA with being overweight/obese in adolescent girls.