Acute Maternal Fasting or Fluid Abstention Does Not Significantly Affect the Macronutrient Composition of Human Milk: Clinical and Clinical Research Relevance

There are guidelines on lactation following maternal analgo-sedative exposure, but these do not consider the effect of maternal fasting or fluid abstention on human milk macronutrient composition. We therefore performed a structured search (PubMed) on ‘human milk composition’ and screened title, abstract and full paper on ‘fasting’ or ‘abstention’ and ‘macronutrient composition’ (lactose, protein, fat, solids, triglycerides, cholesterol). This resulted in six papers and one abstract related t

Phenobarbital Increases Midazolam Clearance in Neonates Treated with Hypothermia: Do We Really Need to Know?

The clinical management and subsequent outcome of pediatric and neonatal patients can improve significantly with the availability of effective and safe medicines if appropriately investigated in the relevant population [1]. This is also the case for neonates treated with hypothermia for perinatal asphyxia. However, the vast majority of medicines are developed with adult pathophysiology in mind and are not guided by neonatal (patho)physiology. Drug development is mainly driven by adult indications, subsequently tailored or repurposed for use in neonates, with exogenous surfactant as the latest but hopefully not last example of drug discovery specific to neonates [2]

Gas Component Transport Across the Soil-Atmosphere Interface for Gases of Different Density: Experiments and Modeling

We investigate the influence of near-surface wind conditions on subsurface gas transport and on soil-atmosphere gas exchange for gases of different density. Results of a sand tank experiment are supported by a numerical investigation with a fully coupled porous medium-free flow model, which accounts for wind turbulence. The experiment consists of a two-dimensional bench-scale soil tank containing homogeneous sand and an overlying wind tunnel. A point source was installed at the bottom of the tank. Gas concentrations were measured at multiple horizontal and vertical locations. Tested conditions include four wind velocities (0.2/1.0/2.0/2.7 m/s), three different gases (helium: light, nitrogen: neutral, and carbon dioxide: heavy), and two transport cases (1: steady-state gas supply from the point source; 2: transport under decreasing concentration gradient, subsequent to termination of gas supply). The model was used to assess flow patterns and gas fluxes across the soil surface. Results demonstrate that flow and transport in the vicinity of the surface are strongly coupled to the overlying wind field. An increase in wind velocity accelerates soil-atmosphere gas exchange. This is due to the effect of the wind profile on soil surface concentrations and due to wind-induced advection, which causes subsurface horizontal transport. The presence of gases with pronounced density difference to air adds additional complexity to the transport through the wind-affected soil layers. Wind impact differs between tested gases. Observed transport is multidimensional and shows that heavy as well as light gases cannot be treated as inert tracers, which applies to many gases in environmental studies. © 2020. The Authors

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

Therapeutic hypothermia (TH) is standard treatment for neonates (≥36 weeks) with perinatal asphyxia (PA) and hypoxic–ischemic encephalopathy. TH reduces mortality and neurodevelopmental disability due to reduced metabolic rate and decreased neuronal apoptosis. Since both hypothermia and PA influence physiology, they are expected to alter pharmacokinetics (PK). Tools for personalized dosing in this setting are lacking. A neonatal hypothermia physiology-based PK (PBPK) framework would enable precision dosing in the clinic. In this literature review, the stepwise approach, benefits and challenges to develop such a PBPK framework are covered. It hereby contributes to explore the impact of non-maturational PK covariates. First, the current evidence as well as knowledge gaps on the impact of PA and TH on drug absorption, distribution, metabolism and excretion in neonates is summarized. While reduced renal drug elimination is well-documented in neonates with PA undergoing hypothermia, knowledge of the impact on drug metabolism is limited. Second, a multidisciplinary approach to develop a neonatal hypothermia PBPK framework is presented. Insights on the effect of hypothermia on hepatic drug elimination can partly be generated from in vitro (human/animal) profiling of hepatic drug metabolizing enzymes and transporters. Also, endogenous biomarkers may be evaluated as surrogate for metabolic activity. To distinguish the impact of PA versus hypothermia on drug metabolism, in vivo neonatal animal data are needed. The conventional pig is a well-established model for PA and the neonatal Göttingen minipig should be further explored for PA under hypothermia conditions, as it is the most commonly used pig strain in nonclinical drug development. Finally, a strategy is proposed for establishing and fine-tuning compound-specific PBPK models for this application. Besides improvement of clinical exposure predictions of drugs used during hypothermia, the developed PBPK models can be applied in drug development. Add-on pharmacotherapies to further improve outcome in neonates undergoing hypothermia are under investigation, all in need for dosing guidance. Furthermore, the hypothermia PBPK framework can be used to develop temperaturedriven PBPK models for other populations or indications. The applicability of the proposed workflow and the challenges in the development of the PBPK framework are illustrated for midazolam as model drug

Rat interleukin-2-activated natural killer (A-NK) cell-mediated lysis is determined by the presence of CD18 on A-NK cells and the absence of major histocompatibility complex class I on target cells

The precise mechanism by which target cells are recognized and subsequently lysed by interleukin-2-activated natural killer (A-NK) cells is poorly understood. In this study the role of major histocompatibility complex (MHC) class I and adhesion molecules in the recognition and lysis of tumor cells was investigated in a syngeneic Wag rat model. Preincubation of tumor cells with F(ab′)2 fragments of anti-MHC class I monoclonal antibody (mAb) OX18 strongly enhanced the A-NK cell-mediated lysis. Also normal syngeneic cells such as T cells and A-NK cells became highly sensitive for lysis by A-NK cells after preincubation with mAb OX18. Two other mAb against MHC class I had no effect on lysis of target cells. These data indicate that masking of MHC class I on syngeneic tumor and normal cells by mAb OX18 is sufficient for A-NK cells to recognize target cells as non-self, resulting in lysis. In addition, we found that the presence of mAb against the β2 (CD18)-integrins blocked the lysis of all tumor cell lines by A-NK cells in 51Cr-release assays, also when target cells were preincubated with mAb OX18. Because of the absence of CD18 on most tumor cells we concluded that a CD18-associated integrin on A-NK cells is essential for lysis of target cells. These results show that in this syngeneic rat model CD18 on A-NK cells together with MHC class I on tumor cells determine A-NK cell-mediated lysis. Furthermore, we hypothesize that the anti-MHC class I OX18 recognizes an epitope on rat MHC class I which is, or is very close to, the restriction element determining A-NK cell-mediated lysis

Different Vancomycin Immunoassays Contribute to the Variability in Vancomycin Trough Measurements in Neonates

Substantial interassay variability (up to 20%) has been described for vancomycin immunoassays in adults, but the impact of neonatal matrix is difficult to quantify because of blood volume constraints in neonates. However, we provide circumstantial evidence for a similar extent of variability. Using the same vancomycin dosing regimens and confirming similarity in clinical characteristics, vancomycin trough concentrations measured by PETINIA (2011-2012, n = 400) were 20% lower and the mean difference was 1.93 mg/L compared to COBAS (2012-2014, n = 352) measurements. The impact of vancomycin immunoassays in neonatal matrix was hereby suggested, supporting a switch to more advanced techniques (LC-MS/MS)

Amikacin or vancomycin exposure alters the postnatal serum creatinine dynamics in extreme low birth weight neonates

Background: Disentangling renal adverse drug reactions from confounders remains a major challenge to assess causality and severity in neonates, with additional limitations related to the available tools (modified Kidney Disease Improving Global Outcome, or Division of Microbiology and Infectious Diseases pediat

Creatinine Trends to Detect Ibuprofen-Related Maturational Adverse Drug Events in Neonatal Life: A Simulation Study for the ELBW Newborn

Background: Recognizing a change in serum creatinine concentrations is useful to detect a renal adverse drug reaction signal. Assessing and characterizing the nephrotoxic side-effects of drugs in extremely low birth weight (ELBW, ≤1000 g) neonates remain challenging due to the high variability in creatinine in this population. This study aims to investigate and quantify the impact of ibuprofen treatment on kidney function, reflected by serum creatinine. Method: A recently developed dynamical model for serum creatinine was used to simulate creatinine profiles for typical, reference ELBW neonates with varying gestational and postnatal ages whilst being exposed to ibuprofen treatment. Results: The increase of serum creatinine concentrations due to ibuprofen treatment is most apparent during the first week of life. The difference in serum creatinine values between ibuprofen-exposed vs. non-exposed neonates decreases with increasing postnatal age, independent of gestational age. Conclusion: The difference in serum creatinine concentrations between ibuprofen-exposed vs. non-exposed neonates decreases with postnatal age, indicating an increased clearing capacity and resulting in a weak ibuprofen-related adverse drug reaction signal beyond early neonatal life