Current Pharmaceutical Design - Volume 18, Issue 21, 2012

The ‘omics’ technologies represent analytical approaches that have a holistic view on molecules such as genes, transcripts, proteins and metabolites constituting a cell, tissue or organism. The profiling of genes, transcripts and proteins has been referred to as genomics, transcriptomics and proteomics. Finally, there is the youngest and most rapidly increasing of the “omics” disciplines: metabolomics. Metabolomics appears to be a new, very useful tool in neonatology, especially in the fields of pharma-metabolomics and nutri- metabolomics. Since it appears to be predictive and preventive, it can be considered the ‘new clinical chemistry’ for personalized neonatal medicine. At present, the use of metabolomics in neonatology is still in the pioneering phase. In clinical practice, only a limited number of metabolites are routinely measured in the biofluids of newborns by conventional analytical methods to study the metabolic status of the organism. However, the management of sick or preterm newborns might be improved if more information on perinatal/neonatal maturational processes and their metabolic background were available. The aim of this review, after a general introduction on pharma-metabolomics, is to present the potential of NMR-based metabolomic analysis of newbom urine in neonatology in the field of pharmacology.

The patency of the ductus arteriosus has ever been considered as a pathological situation in preterm infants and one likely cause of mortality and morbidity, including broncho-pulmonary dysplasia, necrotizing enterocolitis, intraventricular haemorrhage, retinopathy of prematurity. The incidence of patent ductus arteriosus is inversely proportional to gestational age and infants with the lowest gestational ages are the most exposed to the complications of prematurity. So, associations between patent ductus arteriosus and the other morbidities may not be causative and patent ductus arteriosus could be more a sign of immaturity and severity of disease than the cause of these problems. Non-steroidal anti-inflammatory agents, such as indomethacin or ibuprofen, have been shown to be effective in closing or preventing patent ductus arteriosus, with differences in side effects. However nearly all randomized controlled trials have been designed with the closure of the ductus arteriosus, not mortality or morbidity, as the main endpoint. Thus, evidence is still lacking on the eventual benefits for the patient of pharmacological or surgical intervention on PDA. Moreover, both ibuprofen and indomethacin efficacy seems markedly reduced in extremely low gestational age infants, who are the most likely to benefit from such intervention. The explanation of the reduced pharmacodymanic effect in such population is unclear; so far, studies using increased dosing of ibuprofen have failed to show a clear benefit. Prophylaxis with indomethacin or ibuprofen has failed to show sustained benefits on neurodevelopment at 2 years of age in low gestational age infants. New curative trials may aim at investigating the effects of early curative administration of ibuprofen, which has reduced side effects compared to indomethacin, on immature kidney function, on mortality and morbidity in very low gestational age infants, ideally with a combined endpoint such as survival in the absence of severe neurodevelopmental alteration at 2 years age. Despite an understandable reluctance given the historical background of systematic, therapeutic closure of ductus arteriosus in preterm infants, there are no definite ethical obstacles to a placebo-controlled design.

Antiplatelet agents are administered in the treatment of a large number of adult diseases: coronary heart disease, ischemic stroke, peripheral arterial disease, arrhythmias with their thromboembolic complications, primary and secondary prevention. In childhood however, the situation is substantially different. The lack of large interventional trials on the use of antiplatelet drugs in children, has led to greater uncertainty, and a less extensive use of these drugs, limited to fewer indications. The purpose of this article was to review the studies conducted to date on the use of antiplatelet agents in children. A concerted effort has been made to identify which are the shared therapeutic indications of this class of compounds, the recommended dose, the contraindications and the possible side effects. In brief, an attempt has been made to ascertain the interesting potential of these drugs which are so often neglected in children.

Persistent pulmonary hypertension of the newborn (PPHN) is a serious and potentially fatal condition, characterized by hypoxemia due to increased pulmonary vascular resistance (PVR) with resultant shunting of pulmonary blood to the systemic circulation. Inhaled nitric oxide (iNO) has been considered a revolutionary treatment of PPHN. Data show that the use of iNO has reduced the need of ECMO in neonates with severe PPHN, while in moderate PPHN, iNO administration has been associated with a significant decrease in ventilatory support and prevented progression to severe PPHN. Not all neonates respond to iNO therapy though, and phosphodiesterase (PDE) inhibitors with their potent vasodilator properties have evolved as an alternative therapy or as an adjunct to the treatment of PPHN with iNO. There are ten families of PDE isoenzymes. PDE 5 is particularly prevalent in vascular smooth muscle (VSM) and PDE 5 inhibitors, such as sildenafil, have been used in clinical practice. This review provides a comprehensive account of existing data in the literature, from animal and clinical studies, on the use of sildenafil for the treatment of PPHN. Sildenafil may also have a role as a single mode of therapy, since in resource-limited settings the cost of iNO is a serious concern.

Transient tachypnea of the newborn results from delayed clearance of lung fluid and is a common cause of admission of full term and late preterm infants to neonatal intensive care units. The condition is particularly common after elective cesarean section. Conventional treatment involves supplemental oxygen, withholding enteral feeds and administration of intravenous fluids and antibiotics. Rarely, infants require CPAP and mechanical ventilation. Occasionally some babies develop severe hypoxemia and may require high concentrations of oxygen. The most effective strategy for accelerating reabsorbtion of fetal lung fluid is exogenous glucocorticoids. Potential therapies for TTN must be based on an understanding of the physiology of normal fetal lung fluid clearence at bith. Furosemide, racemic epinephrine and inhaled β-agonists have been studied for possible benefit in TTN. The routine administration of these drugs can not be recommended unless additional data become available.

The result of the use of drugs in the newborn may be strongly influenced by the peculiar state of the neonate, characterized by the immaturity, at birth, of the processes controlling the absorption, distribution, metabolism and excretion of drugs. Additional important factors that may affect drugs’ bioavailability and toxicity are gestational age, birth weight, intrauterine growth restriction, gender and, especially, liver function immaturity. Because of the high susceptibility to infections, antibiotics, in particular ampicillin and gentamicin, are the most widely used drugs in newborns. Erythromycin is often used for the therapy of gastrointestinal dismotility, while azithromycin has been proposed for the prevention of bronchopulmonary dysplasia. Prostaglandin synthesis inhibitors, like indomethacin, are administered on the first days of life to close the patent ductus arteriosus. All these drugs have been proved to can give rise to hepatotoxicity. The acute and chronic liver toxicity due to the most widely used drugs in the neonates will be here reviewed.

Release of acetylcholine from parasympathetic nerves in the airways activates postjunctional muscarinic receptors present on smooth muscle, submucosal glands and blood vessels. This triggers bronchoconstriction, muscle hypertrophy, mucus secretion, and vasodilatation, respectively. The release of acetylcholine from parasympathetic nerves in lungs is induced by a variety of stimuli and downregulated by the inhibitory activity of neuronal M2 muscarinic receptors via a feedback mechanism. Increased parasympathetic nerve activity occurs in a variety of airway diseases in childhood, including viral-induced wheeze and asthma. Common to these conditions are reversible airway obstruction, mucus hypersecretion, vasodilation and enhanced vascular permeability. In animal models of airway hyperreactivity similar findings of increased acetylcholine release resulting in enhanced supply of this neurotransmitter to the postjunctional smooth muscles, submucosal glands and airway vessels, were demonstrated. While the number and function of postjunctional muscarinic receptors in the airways are unchanged in such airway disorders, inhibitory activity on the parasympathetic nerves appears to be impaired. Specifically, M2 muscarinic receptor dysfunction has been demonstrated in models of bronchial hyperreactivity induced by a variety of triggers, including viruses, atmospheric pollutants and allergens. The mechanisms leading to impairment of neuronal M2 muscarinic receptor function and their putative relevance to the pathogenesis and the treatment of airway disease in childhood are described. Finally, the available data on the activity of ipratropium bromide, a short-acting anticholinergic drug, in the most common pediatric airway disease are reported and the possible therapeutic efficacy of tiotropium bromide, a more recently introduced long-acting, selective anticholinergic compound, is discussed.

New knowledge of the pathophysiology and evolution of hypoxic-ischemic brain injuries has made feasible interventions to improve clinical outcomes for newborns surviving birth asphyxia. Brain injury following hypoxic-ischemic insult is a complex process evolving over hours to days, which provides a unique window of opportunity for neuroprotective treatment interventions. The specific pathologic processes preceding the onset of irreversible cerebral injury appear to be a combination of several mechanisms that are variable according to the severity and duration of the insult and to biochemical modifications in the brain. Advances in neuroimaging, brain monitoring techniques, and tissue biomarkers have improved the ability to diagnose, monitor, and care for newborn infants with neonatal encephalopathy, as well as to predict their outcome. The role of oxidative stress in newborn morbidity with respect to the higher risk of free radical damage in these babies is growing. However, challenges remain in early identification of infants at risk for neonatal encephalopathy, determination of timing and extent of hypoxic-ischemic brain injury, as well as optimal management and treatment duration. Potential neuroprotective strategies targeting different pathways leading to neuronal cell death in response to hypoxic-ischemic insult have been investigated: hypothermia, erythropoietin, iminobiotin, deferioxamine, magnesium, allopurinol, xenon, melatonin and statins. Hypothermia is currently the only recognized beneficial therapy. However, many infants still develop significant adverse outcomes. It is becoming evident that the association of moderate hypothermia with neuroprotective drugs may enhance the outcome. By virtue of their pleiotropic effects without toxic effects, melatonin and statins may act at different levels of the multiple mechanisms responsible for the progression of the neurodegenerative process and represent promising neuroprotectants, alone or as additional adjunctive therapy, for reducing brain injury and its long-term sequelae in infants. More clinical studies are needed to clarify the role of these potential neuroprotective drugs.

Bronchopulmonary dysplasia (BPD) remains one of the most serious challenges in the care of the very preterm infants, affecting approximately one-quarter of infants born <1500g birth weight and 30% <1000g. Oxygen toxicity may contribute to its pathogenesis. Vitamin A concentrations are lower in BPD infants which may result in a reduction of the antioxidant protection. It has been found to up regulate genes necessary for fetal lung growth and increase surfactant production in animal models and is also involved in the modulation of immunological and inflammatory responses by regulation of cytokine production. Retinoic acid plays a key role in lung development improving alveolar septation. Evidence exists that vitamin A supplementation for very low birth weight (VLBW) infants, beyond that routinely given in multivitamin preparations, is associated with a reduction in death or BPD. So, parenteral administration of vitamin A to the newborn is one of the current recommended preventive therapies for BPD (number needed to treat 12; 95% CI: 6-94; The information on long-term neurodevelopmental status suggests no evidence of either benefit or harm. Estimates for cerebral palsy range from a number needed to treat of 11 to a number needed to harm of 33. Nowadays, it seems that administration of antenatal vitamin A to the mother in late pregnancy associated with neonatal supplementation can better prevent the development of BPD in areas of endemic vitamin A deficiency. The benefits, in terms of vitamin A status, safety and acceptability of delivering vitamin A in an intravenous emulsion compared with repeat intramuscular injections, the association of vitamin A prenatal and postnatal, as well as the effectiveness and safety of administered high dose vitamin A in ELBW infants await evaluation and should be assessed in further trials.

Aminoglycosides have played a major role in antimicrobial therapy since their discovery in the 1940s. Their bactericidal efficacy in gram-negative infections, synergism with beta-lactam antibiotics, limited bacterial resistance, and low cost have given these agents a firm place in antimicrobial treatment. After penicillins, aminoglycosides are the most commonly used drugs in the neonatal intensive care unit. While the pharmacodynamic action on the bacterial target is obviously the same in neonates as compared to children and adults, dramatic differences exist in terms of pharmacokinetics. Renal function is the most important determinant in respect to the elimination of aminoglycosides and, depending on the age and development of the newborn infant, dramatic changes in renal clearing capacity have been documented. The incorporation of this knowledge about the developing kidney has, very recently, resulted in a revised aminoglycoside dosing guideline for use in newborn infants. This article will therefore address the rationale behind this new dosing regimen and also explain why this has resulted in clinically important changes in how to perform therapeutic drug monitoring of aminoglycosides in neonates to ensure safe and effective use of these frequently used medicines in this vulnerable population.

Although the principles of drug disposition also apply in neonates, their specific characteristics warrant focussed assessment. Children display maturation in drug disposition, but this is most prominent in the first year of life. Besides maturational aspects of drug absorption and distribution, maturation mainly relates to (renal) elimination and (hepatic) metabolic clearance. Renal elimination clearance in early life is low and almost completely depends on glomerular filtration. Despite the overall low clearance, interindividual variability is already extensive and can be predicted by covariates like postmenstrual age, postnatal age, co-administration of a non-selective cyclo-oxygenase inhibitor, growth restriction or peripartal asphyxia. These findings are illustrated by observations on amikacin and vancomycin. Variation in phenotypic metabolic clearance is based on constitutional, environmental and genetic characteristics. In early life, it mainly reflects ontogeny, but other covariates may also become relevant. Almost all phase I and phase II metabolic processes display ontogeny in a iso-enzyme specific pattern. The impact of covariates like postmenstrual age, postnatal age, disease state characteristics and polymorphisms are illustrated based or ‘probe’ drugs (paracetamol, tramadol, propofol) administered as part of their medical treatment in critically ill neonates. The description of a compound specific pattern is beyond compound specific relevance. The maturational patterns described and the extent of the impact of covariates can subsequently be applied to predict in vivo time-concentration profiles for compounds that undergo similar routes of elimination. Through improved predictability, such maturational models can serve to improve both the clinical care and feasibility and safety of clinical studies in neonates.