Essential medicines containing ethanol elevate blood acetaldehyde concentrations in neonates.

UNLABELLED: Neonates administered ethanol-containing medicines are potentially at risk of dose-dependent injury through exposure to ethanol and its metabolite, acetaldehyde. Here, we determine blood ethanol and acetaldehyde concentrations in 49 preterm infants (median birth weight = 1190 g) dosed with iron or furosemide, medicines that contain different amounts of ethanol, and in 11 control group infants (median birth weight = 1920 g) who were not on any medications. Median ethanol concentrations in neonates administered iron or furosemide were 0.33 (range = 0-4.92) mg/L, 0.39 (range = 0-72.77) mg/L and in control group infants were 0.15 (range = 0.03-5.4) mg/L. Median acetaldehyde concentrations in neonates administered iron or furosemide were 0.16 (range = 0-8.89) mg/L, 0.21 (range = 0-2.43) mg/L and in control group infants were 0.01 (range = 0-0.14) mg/L. There was no discernible relationship between blood ethanol or acetaldehyde concentrations and time after medication dose. CONCLUSION: Although infants dosed with iron or furosemide had low blood ethanol concentrations, blood acetaldehyde concentrations were consistent with moderate alcohol exposure. The data suggest the need to account for the effects of acetaldehyde in the benefit-risk analysis of administering ethanol-containing medicines to neonates. WHAT IS KNOWN: • Neonates are commonly treated with ethanol-containing medicines, such as iron and furosemide. • However, there is no data on whether this leads to appreciable increases in blood concentrations of ethanol or its metabolite, acetaldehyde. What is New: • In this study, we find low blood ethanol concentrations in neonates administered iron and/or furosemide but markedly elevated blood acetaldehyde concentrations in some infants receiving these medicines. • Our data suggest that ethanol in drugs may cause elevation of blood acetaldehyde, a potentially toxic metabolite.

An observational study of blood concentrations and kinetics of methyl- and propyl-parabens in neonates.

PURPOSE: Systemic exposure to parabens in the neonatal population, in particular propyl-parabens (PPB), remains a concern. Blood concentrations and kinetics of methyl-parabens (MPB) and PPB were therefore determined in neonates receiving medicines containing these excipients. METHODS: A multi-centre, non-interventional, observational study of excipient-kinetics in neonates. 'Dried Blood Spot' samples were collected opportunistically at the same time as routine samples and the observations modelled using a non-linear mixed effects approach. RESULTS: A total of 841 blood MPB and PPB concentration data were available for evaluation from 181 pre- and term-neonates. Quantifiable blood concentrations of MPB and PPB were observed in 99% and 49% of patients, and 55% and 25% of all concentrations were above limit of detection (10 ng/ml), respectively. Only MPB data was amenable to modelling. Oral bioavailability was influenced by type of formulation and disposition was best described by a two compartment model with clearance (CL) influenced by post natal age (PNA); CL PNA<21 days 0.57 versus CL PNA>21 days 0.88 L/h. CONCLUSIONS: Daily repeated administration of parabens containing medicines can result in prolonged systemic exposure to the parent compound in neonates. Animal toxicology studies of PPB that specifically address the neonatal period are required before a permitted daily exposure for this age group can be established.

Risk assessment of neonatal excipient exposure: lessons from food safety and other areas.

Newborn babies can require significant amounts of medication containing excipients intended to improve the drug formulation. Most medicines given to neonates have been developed for adults or older children and contain excipients thought to be safe in these age groups. Many excipients have been used widely in neonates without obvious adverse effects. Some excipients may be toxic in high amounts in which case they need careful risk assessment. Alternatively, it is conceivable that ill-founded fears about excipients mean that potentially useful medicines are not made available to newborn babies. Choices about excipient exposure can occur at several stages throughout the lifecycle of a medicine, from product development through to clinical use. Making these choices requires a scalable approach to analysing the overall risk. In this contribution we examine these issues.

Development and validation of a method for the confirmation of halofuginone in chicken liver and eggs using electrospray tandem mass spectrometry.

A method is described for the quantitative confirmation of halofuginone (HFG) residues in chicken liver and eggs. This method is based on LC coupled to positive ion electrospray MS-MS of the tissue extracts, prepared by trypsin digestion of the tissues followed by liquid-liquid extraction and final clean-up using Solid Phase Extraction (SPE). The [M+H](+) ion at m/z 416 is monitored along with four transitions at m/z 398, 138, 120 and 100. The method has been validated according to the draft EU criteria for the analysis of veterinary drug residues at 15, 30 and 45 microg kg(-1) in liver and 5, 15 and 50 microg kg(-1) in eggs. The new analytical limits, CCalpha and CCbeta were calculated for liver and were 35.4 and 43.6 microg kg(-1), respectively.

Development and validation of a method for the confirmation of nicarbazin in chicken liver and eggs using LC-electrospray MS-MS according to the revised EU criteria for veterinary drug residue analysis.

A method is described for the quantitative confirmation of 4,4'-dinitrocarbanilide (DNC), the marker residue for nicarbazin in chicken liver and eggs. The method is based on LC coupled to negative ion electrospray MS-MS of tissue extracts prepared by liquid-liquid extraction. The [M-H]- ion at m/z 301 is monitored along with two transition ions at m/z 137 and 107 for DNC and the [M-H]- ion at m/z 309 for the internal standard, d8-DNC. The method has been validated according to the new EU criteria for the analysis of veterinary drug residues at 100, 200 and 300 microg kg(-1) in liver and at 10, 30 and 100 microg kg(-1) in eggs. Difficulties concerning the application of the new analytical limits, namely the decision limit (CCalpha) and the detection capability (CCbeta) to the determination of DNC in both liver and eggs are discussed.