Максим Рильський у світлі теорії та практики перекладу

У запропонованій статті проаналізовано актуальні проблеми теорії і практики перекладу у світлі завдань сучасного перекладознавства, зокрема, об’єктом аналізу є переклади М. Т. Рильським визначних творів зі світової літературної скарбниці.В данной статье анализируются актуальные проблемы теории и практики перевода в соответствии с задачами современного переводоведения, в частности, объектом анализа выступают переводы М. Т. Рыльским выдающихся произведений мировой литературы.In the offered article the issues of the day of theory and practice of translation are analysed in the light of tasks of modern translation theory in particular as an object of analysis translations of Maksym Rylski come forward prominent works from a world literary treasury

High accumulation of nivolumab in human breast milk: A case report

Nivolumab is an immunotherapeutic monoclonal antibody (mAb) that is used for the treatment of several types of cancer. The evidence on its use during lactation is lacking. Here, we report on a 39-year-old woman with metastasized melanoma who was treated with 480 mg nivolumab every four weeks during lactation. Breast milk samples were collected over the course of 34 days, including two cycles of nivolumab. The highest measured concentration of nivolumab during the first cycle was 503 ng/mL at day 13. The cumulative relative infant dose (RID) over the first cycle (28 days) was 9.8 %. The highest overall measured nivolumab concentration was 519 ng/mL at day 33, five days after administration of the second nivolumab cycle. Nivolumab seems to accumulate in breast milk over two consecutive cycles, hence the RIDs of consecutive cycles are expected to be higher. To draw further conclusions regarding safety of breastfeeding during nivolumab therapy, more information about the oral bioavailability of nivolumab in newborns, the nivolumab steady-state concentrations in breast milk and its pharmacodynamic effects are needed

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens

Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure–response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies

Pharmacodynamic modeling of cardiac biomarkers in breast cancer patients treated with anthracycline and trastuzumab regimens

Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure–response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab. Repeated measurements of LVEF, troponin T and NT-proBNP and dosing records of anthracyclines and trastuzumab were available from a previously published clinical trial. This trial included 206 evaluable patients with early breast cancer. Exposure to anthracycline and trastuzumab was simulated based on available dosing records and by using a kinetic-pharmacodynamic (K-PD) and a fixed pharmacokinetic (PK) model from literature, respectively. The change from baseline troponin T was described with a direct effect model, affected by simulated anthracycline concentrations, representing myocyte damage. The relationship between trastuzumab and LVEF was described by an indirect effect compartment model. The EC50 for LVEF decline was significantly affected by the maximum troponin T concentration after anthracycline treatment, explaining 15.1% of inter-individual variability. In this cohort, NT-proBNP changes could not be demonstrated to be related to anthracycline or trastuzumab treatment. Pharmacodynamic models for troponin T and LVEF were successfully developed, identifying maximum troponin T concentration after anthracycline treatment as a significant determinant for trastuzumab-induced LVEF decline. These models can help identify patients at risk of drug-induced cardiotoxicity and optimize cardiac monitoring strategies

Population Pharmacokinetics of Docetaxel, Paclitaxel, Doxorubicin and Epirubicin in Pregnant Women with Cancer: A Study from the International Network of Cancer, Infertility and Pregnancy (INCIP)

Background: Based on reassuring short-term foetal and maternal safety data, there is an increasing trend to administer chemotherapy during the second and third trimesters of pregnancy. The pharmacokinetics (PK) of drugs might change as a result of several physiological changes that occur during pregnancy, potentially affecting the efficacy and safety of chemotherapy. Objective: With this analysis, we aimed to quantitatively describe the changes in the PK of docetaxel, paclitaxel, doxorubicin and epirubicin in pregnant women compared with non-pregnant women. Methods: PK data from 9, 20, 22 and 16 pregnant cancer patients from the International Network of Cancer, Infertility and Pregnancy (INCIP) were available for docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. These samples were combined with available PK data from non-pregnant patients. Empirical non-linear mixed-effects models were developed, evaluating fixed pregnancy effects and gestational age as covariates. Results: Overall, 82, 189, 271, and 227 plasma samples were collected from pregnant patients treated with docetaxel, paclitaxel, doxorubicin and epirubicin, respectively. The plasma PK data were adequately described by the respective models for all cytotoxic drugs. Typical increases in central and peripheral volumes of distribution of pregnant women were identified for docetaxel, paclitaxel, doxorubicin and epirubicin. Additionally, docetaxel, doxorubicin and paclitaxel clearance were increased in pregnant patients, resulting in lower exposure in pregnant women compared with non-pregnant patients. Conclusion: Given the interpatient variability, the identified pregnancy-induced changes in PK do not directly warrant dose adjustments for the studied drugs. Nevertheless, these results underscore the need to investigate the efficacy of chemotherapy, when administered during pregnancy

Pharmacokinetic/Pharmacodynamic Modelling of Allopurinol, its Active Metabolite Oxypurinol, and Biomarkers Hypoxanthine, Xanthine and Uric Acid in Hypoxic-Ischemic Encephalopathy Neonates

Background: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. Objective: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. Methods: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. Results: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62–1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25–2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23–0.3) and 11 L (95% CI 9.9–12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31–0.42). Conclusion: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH