Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein).

Learning Objectives After completing this course, the reader will be able to: Identify important sources of variability in drug exposure caused by drug interactions mediated by P-glycoprotein.Describe how unwanted drug–drug interactions may lead to unexpected serious toxicity or undertreatment.Prevent these interactions by individualizing pharmacotherapy; this means selecting noninteracting drugs or adapting the dose of (the) interacting drug(s). CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.co

Specific Investigation of Sample Handling Effects on Protease Activities and Absolute Serum Concentrations of Various Putative Peptidome Cancer Biomarkers

# The Author(s) 2010. This article is published with open access at Springerlink.com Introduction In the search for novel cancer biomarkers, various proteolytically derived peptides have been proposed to exhibit cancer or cancer-type specificity. As these peptides are presumably also generated after sample collection by tumor-specific proteases, extensive investigatio

ABCB1 genotypes and haplotypes in patients with dementia and age-matched non-demented control patients

Amyloid β is an in vitro substrate for P-glycoprotein (P-gp), an efflux pump at the blood brain barrier (BBB). The Multi Drug Resistance (ABCB1) gene, encoding for P-gp, is highly polymorphic and this may result in a changed function of P-gp and may possibly interfere with the pathogenesis of Alzheimer's disease. This study investigates to what extent ABCB1 Single Nucleotide Polymorphisms (SNPs; C1236T in exon 12, G2677T/A in exon 21 and C3435T in exon 26) and inferred haplotypes exist in an elderly population and if these SNPs and haplotypes differ between patients with dementia and age-matched non-demented control patients. ABCB1 genotype, allele and haplotype frequencies were neither significantly different between patients with dementia and age-matched controls, nor between subgroups of different types of dementia nor age-matched controls. This study shows ABCB1 genotype frequencies to be comparable with described younger populations. To our knowledge this is the first study on ABCB1 genotypes in dementia. ABCB1 genotypes are presently not useful as a biomarker for dementia, as they were not significantly different between demented patients and age-matched control subjects

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

Two-stage model-based design of cancer phase I dose escalation trials: evaluation using the phase I program of barasertib (AZD1152)

Introduction Modeling and simulation of pharmacokinetics and pharmacodynamics has previously been shown to be potentially useful in designing Phase I programs of novel anti-cancer agents that show hematological toxicity. In this analysis, a two-stage model-based trial design was evaluated retrospectively using data from the Phase I program with the aurora kinase inhibitor barasertib. Methods Data from two Phase I trials and four regimens were used (n = 79). Using barasertib-hydroxy QPA plasma concentrations and neutrophil count data from only study 1A, a PKPD model was developed and subsequently used to predict the MTD and a safe starting dose for the other trials. Results The PKPD model based on data from the first study adequately described the time course of neutrophil count fluctuation. The two-stage model-based design provided safe starting doses for subsequent phase I trials for barasertib. Predicted safe starting dose levels were higher than those used in two subsequent trials, but lower than used in the other trial. Discussion The two-stage approach could have been applied safely to define starting doses for alternative dosing strategies with barasertib. The limited improvement in efficiency for the phase I program of barasertib may have been due to the fact that starting doses for the studied phase I trials were already nearly optimal. Conclusion Application of the two-stage model-based trial design in Phase I programs with novel anti-cancer drugs that cause haematological toxicity is feasible, safe, and may lead to a reduction in the number of patient treated at sub-therapeutic dose-levels

Расчет параметров гидротранспорта высококонцентрированных гидросмесей в условиях предприятий Кривбасса

Для технології складування на підприємствах Кривбасу відходів збагачення, згущених до концентрації пасти, запропоновано методики розрахунків параметрів та режимів роботи/ гідротранспортних установок з урахуванням гідравлічних та реологічних характеристик.The methods of calculation of parameters and regimes of hydrotransport plants operation for technology of stocking of cleaning rejects condensed till paste concentration at Krivbas enterprises taking into account hydraulic and rheological characteristics are offered

Two-stage model-based clinical trial design to optimize phase I development of novel anticancer agents

Background The phase I program of anticancer agents usually consists of multiple dose escalation studies to select a safe dose for various administration schedules. We hypothesized that pharmacokinetic and pharmacodynamic (PK–PD) modeling of an initial phase I study (stage 1) can be used for selection of an optimal starting dose for subsequent studies (stage 2) and that a post-hoc PK–PD analysis enhances the selection of a recommended dose for phase II evaluation. The aim of this analysis was to demonstrate that this two-stage model-based design, which does not interfere in the conduct of trials, is safe, efficient and effective. Methods PK and PD data of dose escalation studies were simulated for nine compounds and for five administration regimens (stage 1) for drugs with neutropenia as dose-limiting toxicity. PK–PD models were developed for each simulated study and were used to determine a starting dose for additional phase I studies (stage 2). The model-based design was compared to a conventional study design regarding safety (number of dose-limiting toxicities (DLTs)), efficiency (number of patients treated with a dose below the recommended dose) and effectiveness (precision of dose selection). Retrospective data of the investigational anticancer drug indisulam were used to show the applicability of the model-based design. Results The model-based design was as safe as the conventional design (median number of DLTs = 3) and resulted in a reduction of the number of patients who were treated with a dose below the recommended dose (−27%, power 89%). A post-hoc model-based determination of the recommended dose for future phase II studies was more precise than the conventional selection of the recommended dose (root mean squared error 8.3% versus 30%). Conclusions A two-stage model-based phase I design is safe for anticancer agents with dose-limiting myelosuppression and may enhance the efficiency of dose escalation studies by reducing the number of patients treated with a dose below the recommended dose and by increasing the precision of dose selection for phase II evaluation

Ethnic differences in cardiometabolic risk profile in an overweight/obese paediatric cohort in the Netherlands: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Differences in prevalence of cardiometabolic risk factors between different ethnic groups are largely unknown. We determined the variation in cardiometabolic risk profile according to ethnicity in a cohort overweight/obese Dutch children.</p> <p>Methods</p> <p>An oral glucose tolerance test was performed in 516 overweight/obese Dutch children of multi-ethnic origin, attending an obesity out-patient clinic of an urban general hospital (mean age 10.6 ± 3.2; 55.2% boys). Anthropometric parameters and blood samples were collected, and the prevalence of (components of) the metabolic syndrome (MetS) and insulin resistance were determined in each ethnic group.</p> <p>Results</p> <p>Major ethnic groups were Dutch native (18.4%), Turkish (28.1%), and Moroccan (25.8%). The remaining group (27.7%) consisted of children with other ethnicities. Turkish children had the highest mean standardized BMI compared to Dutch native children (<it>P </it>< 0.05). As compared to Moroccan children, they had a higher prevalence of MetS (22.8% vs. 12.8%), low HDL-cholesterol (37.9% vs. 25.8%), hypertension (29.7% vs. 18.0%) and insulin resistance (54.9% vs. 37.4%, all <it>P </it>< 0.05). Although Turkish children also had higher prevalences of forementioned risk factors than Dutch native children, these differences were not statistically significant. Insulin resistance was associated with MetS in the Turkish and Moroccan subgroup (OR 6.6; 95%CI, 2.4–18.3 and OR 7.0; 95%CI, 2.1–23.1, respectively).</p> <p>Conclusion</p> <p>In a Dutch cohort of overweight/obese children, Turkish children showed significantly higher prevalences of cardiometabolic risk factors relative to their peers of Moroccan descent. The prospective value of these findings needs to be established as this may warrant the need for differential ethnic-specific preventive measures.</p