Pharmaceutical research and metabolomics in the newborn.

Newborns are a particularly vulnerable population. The response to a drug in terms of efficacy and toxicity varies widely from one newborn to another. Inter-individual variation in drug response is strongly affected by the patient's biochemical state at the time of therapy, as reflected by his metabolic phenotype, which in turn results from the interaction of both genetic and non-genetic factors. These factors contribute to the difficulties in accurate drug prescribing and dosing and to the increased risk of adverse drug reactions in the neonatal population. Metabolomics has been found to be particularly suitable for pharmaceutical Research & Development, with a range of successful applications that include preclinical safety evaluation of drug candidates, predicting the metabolism and toxicity of a drug based on the analysis of a pre-dose metabolic profile (pharmacometabolomics), and identification of drug-related alterations in metabolic pathways. Pharmacometabolomics is a rapidly developing field which refers to the direct measurement of metabolites in an individual's body fluids to predict or evaluate the metabolism of pharmaceuticals. The implementation of metabolomic techniques in pharmaceutical research has the potential to greatly enhance our understanding of mechanisms of drug effects, of undesirable drug reactions and of the biological processes underlying individual variations in drug response phenotypes. A more extensive clinical use of metabolomics could be a decisive step towards personalized drug therapy, with the ultimate aim to match the right drug to the right patient. Some applications of metabolomics in pharmaceutical research are discussed, with special focus on clinical use in Neonatology.

Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed in pregnancy to treat fever, pain and inflammation. Indications for chronic use of these agents during pregnancy are inflammatory bowel or chronic rheumatic diseases. Since the seventies, NSAIDs have been used as effective tocolytic agents: indomethacin has been the reference drug, delaying delivery for at least 48 hours and up to 7-10 days. Additionally, self-medication with NSAIDs is practiced by pregnant women. NSAIDs given to pregnant women cross the placenta and may cause embryo-fetal and neonatal adverse effects, depending on the type of agent, the dose and duration of therapy, the period of gestation, and the time elapsed between maternal NSAID administration and delivery. These effects derive from the action mechanisms of NSAIDs (mainly inhibition of prostanoid activity) and from the physiological changes in drug pharmacokinetics occurring during pregnancy. Increased risks of miscarriage and malformations are associated with NSAID use in early pregnancy. Conversely, exposure to NSAIDs after 30 weeks' gestation is associated with an increased risk of premature closure of the fetal ductus arteriosus and oligohydramnios. Fetal and neonatal adverse effects affecting the brain, kidney, lung, skeleton, gastrointestinal tract and cardiovascular system have also been reported after prenatal exposure to NSAIDs. NSAIDs should be given in pregnancy only if the maternal benefits outweigh the potential fetal risks, at the lowest effective dose and for the shortest duration possible. This article discusses in detail the placental transfer and metabolism of NSAIDs, and the adverse impact of prenatal NSAID exposure on the offspring.