Estimation of initial phenobarbital dosing in term neonates with moderate-to-severe hypoxic ischaemic encephalopathy following perinatal asphyxia.

WHAT IS KNOWN AND OBJECTIVE: Phenobarbital is the first-line treatment of seizures in asphyxiated neonates; however, due to the high pharmacokinetic variability in this population, there is no consensus on the optimal dosage regimen. This study was conducted to identify variables that affect phenobarbital fate during routine clinical care and then to evaluate the dosage schedule that could be applied in term asphyxiated neonates with respect to achieving the target therapeutic range. METHODS: Phenobarbital pharmacokinetics was calculated based on serum concentrations measurements using one-compartmental model. Body weight, body surface area, gestational age, creatinine clearance, total bilirubin, alanine aminotransferase, aspartate aminotransferase, international normalized ratio, Apgar scores, umbilical cord arterial pH and base excess were explored as covariates in linear regression models. Based on this analysis, phenobarbital loading and maintenance dose regimen were projected. RESULTS AND DISCUSSION: In the whole study population (N = 36), phenobarbital volume of distribution, clearance and half-life median (interquartile range) values were 0.49 (0.38-0.59) L/kg, 0.0045 (0.0034-0.0055) L/h/kg and 75.1 (60.2-103.3) hours, respectively. The drug volume of distribution was associated with body weight, length and body surface area, whereas clearance was not in relationship with any explored features. Weight-normalized loading dose of 15 mg/kg and weight-normalized daily maintenance dose of 3 mg/kg proved to be optimal in our study population to reach phenobarbital therapeutic range. WHAT IS NEW AND CONCLUSIONS: This study presents basis for phenobarbital initial dosing in term asphyxiated neonates during first week of life. Phenobarbital weight-normalized loading dose of 15 mg/kg lead to simulated target peak concentrations in 72% of neonates, weight-normalized maintenance dose of 3 mg/kg lead to steady state within therapeutic window in the same proportion of patients.

Significance of aberrant DNA methylation for cancer diagnostics and therapy.

BACKGROUND: Epigenetics is a scientific field that covers changes in gene expression that are not caused by the alteration of the nucleotide sequence in the DNA strand. Together with sequential changes, epigenetic reprogramming is a recognized cancer hallmark driving carcinogenesis. The underlying mechanisms of epigenetically-driven gene expression changes are diverse. However, one of the most extensively studied mechanisms is a change in DNA methylation. Under physiological conditions, DNA methylation ensures tissue-specific gene silencing and helps to maintain genome stability. With malignant transformation, genomic DNA undergoes global hypomethylation as well as locus-specific hypermethylation in promoters of tumor suppressor genes. In the last few decades, specific aberrant DNA methylation changes have emerged as both cancer-associated biomarkers and therapeutic targets and prompted ongoing efforts to enhance both diagnostic and therapeutic means in oncology. PURPOSE: The main purpose of this review is to introduce both established and emerging DNA methylation-based biomarkers for cancer diagnostics with a focus on biomarkers that are either routinely used or have been developed as commercial tests with certification for their use within in vitro diagnostics. Furthermore, therapeutic options for targeting aberrant DNA methylation are described, including both approved compounds and newly developed agents undergoing clinical investigation.

Particulate matter source apportionment in a village situated in industrial region of Central Europe.

The bilinear receptor model positive matrix factorization (PMF) was used to apportion particulate matter with an aerodynamic diameter of 1-10 microm (PM1-10) sources in a village, Brezno, situated in an industrial region of northern Bohemia in Central Europe. The receptor model analyzed the data sets of 90- and 60-min integrations of PM1-10 mass concentrations and elemental composition for 27 elements. The 14-day sampling campaigns were conducted in the village in summer 2008 and winter 2010. Also, to ensure seasonal and regional representativeness of the data sets recorded in the village, the spatial-temporal variability of the 24-hr PM10 and PM1-10 within 2008-2010 in winter and summer across the multiple sites was evaluated. There were statistically significant interseasonal differences of the 24-hr PM data, but not intrasummer or intrawinter differences of the 24-hr PM1-10 data across the multiple sites. PMF resolved seven sources of PM1-10. They were high-temperature coal combustion; combustion in local heating boilers; marine aerosol; mineral dust; primary biological/wood burning; road dust, car brakes; and gypsum. The main summer factors were assigned to mineral dust (38.2%) and primary biological/wood burning (33.1%). In winter, combustion factors dominated (80%) contribution to PM1-10. The conditional probability function (CPF) helped to identified local sources of PM1-10. The source of marine aerosol from the North Sea and English Channel was indicated by the Hybrid Single Particle Lagrangian Integrated Trajectory Model (HYSPLIT).

[The use of nitric oxide in the treatment of acute respiratory failure]. / NO v lécbe respiracního selhání.

BACKGROUND: Nitric oxide was used as an important selective vasodilator in the treatment of acute respiratory failure accompanied with high pulmonary resistance in children and adults since late 80's. METHODS AND RESULTS: Paper includes remarks about nitric oxide physiology in organism. Group of 33 patients is presented (group I 26 newborns, group II 7 children) in which selective pulmonary vasodilation with nitric oxide was used. According to response to NO subject were classified into subgroups of responders, non-responders. In evaluation of oxygenation status OI (oxygenation index, A-a DO2 (alveoloarterial difference) and paO2/FiO2 were used. CONCLUSIONS: Significant differences of above mentioned values were revealed between responders and non-responders in group I (newborns). Significant differences were not revealed in group II (children). Results are in accordance with other papers.

Sufentanil and midazolam dosing and pharmacogenetic factors in pediatric analgosedation and withdrawal syndrome.

Our aim was to describe the effect of dosing and genetic factors on sufentanil- and midazolam-induced analgosedation and withdrawal syndrome (WS) in pediatric population. Analgosedation and withdrawal syndrome development were monitored using COMFORT-neo/-B scores and SOS score. Length of therapy, dosing of sufentanil and midazolam were recorded. Genotypes of selected candidate polymorphisms in CYP3A5, COMT, ABCB1, OPRM1 and PXR were analysed. In the group of 30 neonates and 18 children, longer treatment duration with midazolam of 141 h (2 - 625) vs. 88 h (7 - 232) and sufentanil of 326.5 h (136 - 885) vs. 92 h (22 - 211) (median; range) was found in the patients suffering from WS vs. non-WS group, respectively. Median midazolam cumulative doses were in the respective values of 18.22 mg/kg (6.93 - 51.25) vs. 9.94 mg/kg (2.12 - 49.83); P=0.03, and the respective values for sufentanil were 88.60 microg/kg (20.21 - 918.52) vs. 21.71 microg/kg (4.5 - 162.29); P<0.01. Cut off value of 177 hours for sufentanil treatment duration represented predictive factor for WS development with 81 % sensitivity and 94 % specificity. SNPs in the candidate genes COMT, PXR and ABCB1 affected the dosing of analgosedative drugs, but were not associated with depth of analgosedation or WS. Cumulative dose and length of analgosedative therapy with sufentanil significantly increases the risk of WS in critically ill neonates and children.

Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns.

Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

Source apportionment of size resolved particulate matter at a European air pollution hot spot.

Positive Matrix Factorization-PMF was applied to hourly resolved elemental composition of fine (PM0.15-1.15) and coarse (PM1.15-10) aerosol particles to apportion their sources in the airshed of residential district, Ostrava-Radvanice and Bartovice in winter 2012. Multiple-site measurement by PM2.5 monitors complements the source apportionment. As there were no statistical significant differences amongst the monitors, the source apportionment derived for the central site data is expected to apply to whole residential district. The apportioned sources of the fine aerosol particles were coal combustion (58.6%), sinter production-hot phase (22.9%), traffic (15%), raw iron production (3.5%), and desulfurization slag processing (<0.5%) whilst road dust (47.3%), sinter production-cold phase (27.7%), coal combustion (16.8%), and raw iron production (8.2%) were resolved being sources of the coarse aerosol particles. The shape and elemental composition of size-segregated aerosol airborne-sampled by an airship aloft presumed air pollution sources helped to interpret the PMF solution.

The Impact of Hypothermia on the Pharmacokinetics of Drugs Used in Neonates and Young Infants.

Therapeutic hypothermia (HT) is frequently used in neonates with hypoxic-ischemic encephalopathy and young infants during cardiopulmonary bypass (CPB). Hypothermia and CPB result in physiological changes contributing to pharmacokinetic (PK) and pharmacodynamic (PD) changes. Changes in the absorption, the volume of distribution (Vd) and the total body clearance (CL) of drugs used during hypothermia and CPB might lead to the interindividual PK variability resulting in either insufficient or toxic plasma concentrations and have an impact on the biodisposition and action of drugs. Both under- or overdosing of medicines in these critically ill patients may contribute to a worse overall outcome. Overall, hypothermia decreases CL but may decrease or increase Vd by changing intravascular blood volume, organ perfusion and enzymatic metabolic processes. In addition, maturational as well as organ specific changes may occur during hypothermia superimposed on the underlying disease and/or procedures such as extracorporeal membrane oxygenation (ECMO) or CPB. This paper will provide an overview of variables and potential covariates (e.g., asphyxia, sepsis, multiorgan dysfunction syndrome, cardiac arrest) determining the PK of frequently used drugs. In addition, the effects of hypothermia on individual drugs are described as well as alternative ways for future study designs such as the use of population PK-PD and opportunistic sampling. Ultimately, these investigations are warranted to obtain specific dosing nomograms of medicines for use in clinical practice and to improve the treatment results of this vulnerable group of pediatric patients.

Prognostic factors in renal cell carcinoma patients treated with sorafenib: results from the Czech registry.

The aim of this study was to describe the characteristics and outcomes of a large cohort of patients treated with sorafenib in clinical practice and to identify predictive factors associated with prognosis. Patient data were obtained from the national Czech registry (RenIS). Data of virtually all Czech patients receiving targeted therapies are entered into this non-interventional post-registration database. Demographics and clinical data, as well as all treatment sequences and clinical outcomes, are reported in this registry. A total of 836 patients treated with sorafenib before March 2013 were included in the analysis. Median age was 63 years and 70% were men. Most patients had received prior treatment with cytokines, sunitinib or both. Sorafenib was the first-line treatment in 15% of patients. Median overall survival and progression-free survival were 21.7 months and 7.5 months, respectively. Median overall survival and progression-free survival was 26.3 and 8.3 months, respectively, in patients receiving sorafenib as first-line therapy. Cox proportional models identified several parameters associated with poor outcome including time ≤1 year from diagnosis to first-line systemic treatment, performance status ≥2, low hemoglobin, and LDH >1.5 times the upper limit of normal. Our data demonstrate that the outcomes of real-life patients are comparable to those enrolled in clinical trials. Prognostic factors identified in the present study were consistent with previously reported models.

[Sodium nitrite poisoning in a neonate]. / Otrava novorozence dusitanem sodným.

Natrium nitrosum intoxication is usually associated with a subsequent methemoglobinemia. Beside it, nitrates can cause also some other pathological states. Treatment with the toluidine blue may have various adverse side effects. Newborn intoxication by natrium nitrosum developing after the intoxication of the bearing mother before the parturition has not been described yet. Our own observation is referred.

Pharmacotherapy in neonatal and pediatric extracorporeal membrane oxygenation (ECMO).

ECMO support is an established life saving therapy for potentially reversible respiratory and/or cardiac failure. Improvement of outcome depends on effective treatment of the primary diagnosis and complications. Adequate drug therapy is important in reaching these goals. Pharmacokinetic and pharmacodynamic data in neonates and older children on ECMO are sparse. Most studies show altered volume of distribution and clearance for the drugs studied. This article gives an overview of the available PK and PD studies in neonates and children on ECMO, suggests possible mechanisms of altered PK and PD and identifies areas of interest for further research.

Challenges in non-neonatal extracorporeal membrane oxygenation.

This review will address the different challenges for the use of non-neonatal extracorporeal membrane oxygenation (ECMO). It will discuss the available evidence for the use of pediatric ECMO in respiratory and circulatory failure, focusing on indications and contra-indications and choice of ECMO mode. Furthermore we will try to define optimal treatment goals, identify primary outcome parameters and calculate the expected need for non-neonatal ECMO per 1.000.000 inhabitants.

Trimepranol increases a negative inotropic effect of MgNa2EDTA in rabbits in vivo.

The effect of a pre-treatment with the chelator MgNa2EDTA (0.5 mg.kg-1 i.v.) on the influencing of cardiac contractility by Trimepranol (0.3 mg.kg-1 i.v.) was studied in rabbits in vivo under pentobarbital anaesthesia in the conditions of the spontaneous and paced heart rates and compared with the effects of the administration of the chelator MgNa2EDTA (0.5 mg.kg-1 i.v.) alone. The administration of the chelator alone induced especially commencing with the end of the first hour of observation, a progressive decrease in the left ventricular dP/dtmax. both in the paced heart (max. 67.0 % in the 170th min) and in the nonpaced heart conditions (max. 60.9 % in the 180th min). The administration of Trimepranol (120 min after the pre-treatment with the chelator) resulted in a pronounced increase in a negative inotropic effect (max. 43.1% in the paced and 35.3 % in the non-paced heart, always in the 130th min, i.e., 10 min after the administration of the beta-blocker), which was in most intervals significantly different from the values of dP/dtmax. after the administration of the chelator alone. A significant increase in the negative inotropic effect was manifested also by deaths of a number of experimental animals before the end of observation. On the basis of the results obtained, it is possible to assume that the combination of the administration of MgNa2EDTA with beta-blockers may especially result in an increase in the cardiodepressive action and in an occurrence of adverse effects on the hemodynamics of the organism.

The possible use for immunohistochemical detection of cells in S-phase labeled by bromodeoxyuridine.

Experiences with the use of bromodeoxyuridine (BrdU) as a marker of cellular division were described within this paper. BrdU is incorporated in the course of S-phase of cell cycle into the arising DNA in place of thymidine. The presence of BrdU in cell nuclei of tested tissues was detected with a monoclonal antibody and immunoperoxidase method. It was found that: 1. In adult rats a total dose of 100 mg is sufficient for labeling nuclei in most tissues, however intensity of the staining varies. The largest amount of BrdU was revealed in enterocyte nuclei. Lower level of BrdU was detected in cells in the spleen and in the interalveolar septa (probably macrophages) and the lowest one was found in the liver (hepatocytes, Kupffer, and Ito cells); with the exception of individual astrocytes no labeling was revealed in the central nervous system. 2. ED14 (14 days old) rat embryo that had been exposed to BrdU in the mother body, revealed only a weak labeling because of the uptake of BrdU in the placenta. The highest level of BrdU was observed in mesenchymal cells surrounding primitive organs. 3. Explants of the cerebral rat ED14 cortex that had been exposed to BrdU during intrauterine development, remain to be BrdU positive even after their transplantation into the recipient's brain. Different intensity of cell nuclei labeling reflects the rate of mitoses from embryonic day 12 (ED12) to ED14 when BrdU had been administered.

The effects of calcium channel blockers on the cardiovascular system of rabbits in vivo.

The effects of i.v. administration of the calcium channel blockers--verapamil (0.045 and 0.45 mg.kg-1) and Mepamil (2-methylphenyl-derivative of verapamil; 0.0445 and 0.445 mg.kg-1) on the cardiovascular system of rabbits in vivo under the paced and non-paced heart conditions were investigated. Verapamil induced--in the dose-dependent manner--a decrease in blood pressure (max. 65.2%), a significant decrease in dP/dtmax. (max. 46.0%), a bradycardia (max. 79.4%), a decrease in minute blood flow (max. 63.9 %) and stroke blood flow (max. 71.5%). The administration of Mepamil did not induce important changes in heart rate; changes in other parameters were--again in the dose-dependent manner--of a similar qualitative character as after verapamil administration, but they were quantitatively less expressed (especially marked in the effect on dP/dtmax, where the maximum decrease was only to 71.5%). The results show a less pronounced cardiodepressive activity of Mepamil compared to verapamil in rabbits.