Gene expression profiles in preterm infants on continuous long­term oxygen therapy suggest reduced oxidative stress­dependent signaling during hypoxia.

Preterm infants are susceptible to neonatal inflammatory/infective diseases requiring drug therapy. The present study hypothesized that mRNA expression in the blood may be modulated by signaling pathways during treatment. The current study aimed to explore changes in global gene expression in the blood from preterm infants with the objective of identifying patterns or pathways of potential relevance to drug therapy. The infants involved were selected based on maternal criteria indicating increased risk for therapeutic intervention. Global mRNA expression was measured in 107 longitudinal whole blood samples using Affymetrix Human­Genome­U133 Plus 2.0­arrays; samples were obtained from 20 preterm infants. Unsupervised clustering revealed a distinct homogeneous gene expression pattern in 13 samples derived from seven infants undergoing continuous oxygen therapy. At these sampling times, all but one of the seven infants exhibited severe drops in peripheral capillary saturation levels below 60%. The infants were reoxygenated with 100% inspired oxygen concentration. The other samples (n=94) represented the infants from the cohort at time points when they did not undergo continuous oxygen therapy. Comparing these two sets of samples identified a distinct gene expression pattern of 5,986 significantly differentially expressed genes, of which 5,167 genes exhibited reduced expression levels during transient hypoxia. This expression pattern was reversed when the infants became stable, i.e., when they were not continuously oxygenated and had no events of hypoxia. To identify signaling pathways involved in gene regulation, the Database for Annotation, Visualization and Integrated Discovery online tool was used. Mitogen­activated protein kinases, which are normally induced by oxidative stress, exhibited reduced gene expression during hypoxia. In addition, nuclear factor erythroid 2­related factor 2­antioxidant response element target genes involved in oxidative stress protection were also expressed at lower levels, suggesting reduced transcription of this pathway. The findings of the present study suggest that oxidative stress­dependent signaling is reduced during hypoxia. Understanding the molecular response in preterm infants during continuous oxygenation may aid in refining therapeutic strategies for oxygen therapy.

Probable topiramate-induced diarrhea in a 2-month-old breast-fed child - A case report.

An infant developed a severe condition of recurrent and persistent watery diarrhea at 40 days of age. The child had been partially breast-fed, and the mother used topiramate for epilepsy. Hospital examination excluded a viral or bacterial infection and failed to identify any other potential cause. After two weeks, topiramate exposure was suspected to be the cause, and breast-feeding was suspended. The diarrhea ceased within 2 days. Analysis of the breast milk showed a topiramate concentration of 15.7 µmol/L (5.3 µg/mL). There is little information on the use of topiramate in breast-feeding women. The potential effects on the children are not known. Topiramate passes into breast milk, and the concentration may equal the therapeutic plasma concentration. In this case, the infant may have ingested up to 40% of the mother's weight-adjusted dose. Diarrhea is a well-known adverse reaction to topiramate and has the potential to cause serious electrolyte disturbances in neonates and infants. The condition improved rapidly after suspension of breast-feeding. Topiramate in breast milk may reach levels that cause adverse effects in infants. Based on the adverse reaction profile of topiramate and the milk concentration, the diarrhea was assessed as a probable adverse drug reaction in the infant.

Compatibility of drug infusions in the NICU.

OBJECTIVES: The majority of drugs used in sick newborns receiving intensive care are unlicensed and off-label, exposing infants to greater risk of adverse drug reactions (ADRs). Our aim was to study the compatibility of co-infusions for a selected group of drugs and nutrition solutions as part of our quality assurance programme in the neonatal intensive care unit. METHODS: The authors reviewed drug studies in the literature. Documented compatibility or the lack thereof was the main end point for the 1042 co-infusions investigated. The results of searches were reviewed against predetermined criteria for co-infusion of 13 intensive care drugs with 66 other drugs and two nutrition solutions and albumin. RESULTS: 33/820 (4%) co-infusions were documented as compatible without any restrictions. 212/820 (26%) drug co-infusions were compatible, but 196 of the 212 (93%) had restrictions on infusion fluid, concentration or contact time. 608/820 (74%) drug co-infusions in neonates have either been shown to be incompatible or have not been tested. Among those not tested, 163/486 (34%) entailed major differences in pH level which could cause co-infusion instability. CONCLUSION: There is a lack of data on compatibility for the majority of drugs used for co-infusions in neonates. Caregivers therefore need to pay special attention to infusion lines when drugs are co-administered. Our results suggest that further studies on drug compatibility are needed to reduce possible ADRs and toxicity, and avoid precipitation and occlusion of infusion lines in critically ill neonates.

Dosage and formulation issues: oral vitamin E therapy in children.

PURPOSE: Oral vitamin E is used in several childhood diseases, but dosage recommendations differ. Few oral products have a marketing authorization for therapeutic use in children. Preliminary data indicate differences in bioavailability among the various vitamin E compounds. Our objective was to review published data on oral vitamin E therapy in neonates and children in order to establish dosage recommendations at a local level. METHODS: A literature search was conducted, including Medline Ovid, EMBASE (1980-Feb 2008), Cochrane databases, product monographs, handbooks, and textbooks. RESULTS: The main vitamin E compounds being used in children are alpha-tocopherol, alpha-tocopheryl acetate, and tocofersolan. The most data are available on tocopheryl acetate, both in neonates and older children. In children with malabsorption disorders, tocofersolan appears to have an increased bioavailability compared to tocopherol or tocopheryl acetate. Published data on pharmacokinetics and dosages for clinical use are few and heterogeneous. No pharmacokinetic studies were found for tocofersolan in neonates and infants. There are few comparative studies on pharmacokinetics, therapeutic use, and adverse drug reactions (ADRs) in children. Dosages used in clinical studies and dosage recommendations in handbooks differ considerably. CONCLUSIONS: The differences in dosing recommendations in children may be due to lack of systematic studies. Existing published data on oral vitamin E do not provide a basis for evaluation of dosage recommendations in children. Comparative clinical studies are required for scientific evaluation of pharmacokinetics, dosage regimens, and efficacy/ADR assessments in children.

[Vitamin E mixture for children--treatment with a blindfold?]. / Vitamin E-mikstur til barn--behandling i blinde?

BACKGROUND: Vitamin E is used in children with different diagnoses and conditions, including premature babies and infants. In Norway, there is no licensed vitamin E formulation designed for children. Consequently, extemporaneous production is carried out in pharmacies. Two formulation recipes are available, one for veterinary use and one intended for premature infants. MATERIAL AND METHODS: A questionnaire was sent to all Norwegian hospital pharmacies to examine what type of oral vitamin E drops that had been produced or procured after 1 January 2003. RESULTS: 27 (90%) of 30 hospital pharmacies replied. 18 (66.6%) had produced or procured vitamin E drops. 11 (40.7%) had produced or procured a product similar to Vitamin E 50 mg/ml drops for veterinary use. Nine (33.3 %) had produced or procured a product similar to the product called Vitamin E 50 IE/ml drops for premature infants. INTERPRETATION: Data on the various vitamin E formulations, concentrations, optimal dosing and toxicity lack consistency. Lack of data may cause sub-optimal treatment, adverse reactions, or overdosing.