Molecular mechanisms of oxidative stress-related neonatal jaundice.

Oxidative stress is a pathological condition characterized by an overload of oxidant products, named free radicals, which are not well counteracted by antioxidant systems. Free radicals induce oxidative damage to many body organs and systems. In neonatal red blood cells, free-radical mediated-oxidative stress leads to eryptosis, a suicidal death process of erythrocytes consequent to alteration of cell integrity. Neonatal red blood cells are targets and at the same time generators of free radicals through the Fenton and Haber-Weiss reactions. Enhanced eryptosis in case of oxidative stress damage may cause anemia if the increased loss of erythrocytes is not enough compensated by enhanced new erythrocytes synthesis. The oxidative disruption of the red cells may cause unconjugated idiopathic hyperbilirubinemia in neonates. High levels of bilirubin are recognized to be dangerous for the central nervous system in newborns, however, many studies have highlighted the antioxidant function of bilirubin. Recently, it has been suggested that physiologic concentration of bilirubin correlates with higher antioxidant status while high pathological bilirubin levels are associated with pro-oxidants effects. The aim of this educational review is to provide an updated understanding of the molecular mechanisms underlying erythrocyte oxidant injury and its reversal in neonatal idiopathic hyperbilirubinemia.

Neurotrophins: Expression of Brain-Lung Axis Development.

Neurotrophins (NTs) are a group of soluble growth factors with analogous structures and functions, identified initially as critical mediators of neuronal survival during development. Recently, the relevance of NTs has been confirmed by emerging clinical data showing that impaired NTs levels and functions are involved in the onset of neurological and pulmonary diseases. The alteration in NTs expression at the central and peripheral nervous system has been linked to neurodevelopmental disorders with an early onset and severe clinical manifestations, often named "synaptopathies" because of structural and functional synaptic plasticity abnormalities. NTs appear to be also involved in the physiology and pathophysiology of several airway diseases, neonatal lung diseases, allergic and inflammatory diseases, lung fibrosis, and even lung cancer. Moreover, they have also been detected in other peripheral tissues, including immune cells, epithelium, smooth muscle, fibroblasts, and vascular endothelium. This review aims to provide a comprehensive description of the NTs as important physiological and pathophysiological players in brain and lung development.

Vascular Endothelial Growth Factor as Molecular Target for Bronchopulmonary Dysplasia Prevention in Very Low Birth Weight Infants.

Bronchopulmonary dysplasia (BPD) still represents an important burden of neonatal care. The definition of the disease is currently undergoing several revisions, and, to date, BPD is actually defined by its treatment rather than diagnostic or clinic criteria. BPD is associated with many prenatal and postnatal risk factors, such as maternal smoking, chorioamnionitis, intrauterine growth restriction (IUGR), patent ductus arteriosus (PDA), parenteral nutrition, sepsis, and mechanical ventilation. Various experimental models have shown how these factors cause distorted alveolar and vascular growth, as well as alterations in the composition and differentiation of the mesenchymal cells of a newborn's lungs, demonstrating a multifactorial pathogenesis of the disease. In addition, inflammation and oxidative stress are the common denominators of the mechanisms that contribute to BPD development. Vascular endothelial growth factor-A (VEGFA) constitutes the most prominent and best studied candidate for vascular development. Animal models have confirmed the important regulatory roles of epithelial-expressed VEGF in lung development and function. This educational review aims to discuss the inflammatory pathways in BPD onset for preterm newborns, focusing on the role of VEGFA and providing a summary of current and emerging evidence.

A Randomized, Controlled Trial to Investigate the Efficacy of Nebulized Poractant Alfa in Premature Babies with Respiratory Distress Syndrome.

OBJECTIVE: To investigate the efficacy and safety of nebulized poractant alfa (at 200 and 400 mg/kg doses) delivered in combination with nasal continuous positive airway pressure compared with nasal continuous positive airway pressure alone in premature infants with diagnosed respiratory distress syndrome. STUDY DESIGN: This randomized, controlled, multinational study was conducted in infants at 280/7 to 326/7 weeks of gestation. The primary outcome was the incidence of respiratory failure in the first 72 hours of life, defined as needing endotracheal surfactant and/or mechanical ventilation owing to prespecified criteria. Secondary outcomes included the time to respiratory failure in the first 72 hours, duration of ventilation, mortality, incidence of bronchopulmonary dysplasia, and major associated neonatal comorbidities. In addition, the safety and tolerability of the treatments were assessed reporting the number and percentage of infants with treatment-emergent adverse events and adverse drug reactions during nebulization. RESULTS: In total, 129 infants were randomized. No significant differences were observed for the primary outcome: 24 (57%), 20 (49%), and 25 (58%) infants received endotracheal surfactant and/or mechanical ventilation within 72 hours in the poractant alfa 200 mg/kg, poractant alfa 400 mg/kg, and nasal continuous positive airway pressure groups, respectively. Similarly, secondary respiratory outcomes did not differ among groups. Enrollment was halted early owing to a change in the benefit-risk balance of the intervention. Nebulized poractant alfa was well-tolerated and safe, and no serious adverse events were related to the study treatment. CONCLUSIONS: The intervention did not decrease the likelihood of respiratory failure within the first 72 hours of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03235986.

The care of critically ill infants and toddlers in neonatal intensive care units across Italy and Europe: our proposal for healthcare organization.

Numerous studies have shown that critically ill infants and toddlers admitted to paediatric intensive care units (PICUs) have a lower mortality than those admitted to adult ICUs. In 2014, there were only 23 registered PICUs in Italy, most of which were located in the north. For this reason, in Italy and elsewhere in Europe, some neonatal ICUs (NICUs) have begun managing critically ill infants and toddlers. Our proposal for healthcare organization is to establish "extended NICUs" in areas where paediatric intensive care beds are lacking. While some countries have opted for a strict division between neonatal and paediatric intensive care units, the model of "extended NICUs" has already been set up in Italy and in Europe. In this instance, the management of critically ill infants and toddlers undoubtedly falls upon neonatologists, who, however, must gain specific knowledge and technical skills in paediatric critical care medicine (PCCM). Postgraduate residencies in paediatrics need to include periods of specific training in neonatology and PCCM. The Italian Society of Neonatology's Early Childhood Intensive Care Study Group is supporting certified training courses for its members involving both theory and practice. CONCLUSION: Scientific societies should promote awareness of the issues involved in the intensive management of infants and toddlers in NICUs and the training of all health workers involved. These societies include the Italian Society of Neonatology, the European Society of Paediatric and Neonatal Intensive Care, and the Union of European Neonatal and Perinatal Societies. They should also act in concert with the governmental institutional bodies to establish the standards for the "extended NICUs." WHAT IS KNOWN: • The mortality of critically ill infants and toddlers admitted to PICUs is lower than that for those admitted to adult ICUs. • In Italy, there are only a handful of PICUs, located mainly in the north. WHAT IS NEW: • Critically ill infants and small toddlers can be managed in "extended NICUs" in areas with a lack of paediatric intensive care beds. • "Extended NICUs" is our proposal for healthcare organization to compensate for the paucity of paediatric intensive care beds, but neonatologists must be trained to provide them with specific knowledge and technical skills in PCCM.

Hemophagocytic lymphohistiocytosis following gene replacement therapy in a child with type 1 spinal muscular atrophy.

WHAT IS KNOWN AND OBJECTIVE: Onasemnogene abeparvovec (OA) is the first gene replacement therapy for the treatment of paediatric patients with bi-allelic mutations in the SMN1 gene. Efficacy and safety of OA have been assessed in several studies with promising results, despite rare side effects have been described. CASE SUMMARY: A 3-year-old child with spinal muscular atrophy was treated with OA and subsequently developed fever, widespread erythematous skin lesions and hepatosplenomegaly. Laboratory tests were suggestive for Hemophagocytic lymphohistiocytosis (HLH). WHAT IS NEW AND CONCLUSION: To our knowledge, this is the first case of HLH following gene replacement therapy with OA, described in literature.

Melatonin Administration from 2000 to 2020 to Human Newborns with Hypoxic-Ischemic Encephalopathy.

Hypoxic-ischemic encephalopathy (HIE) is the main cause of long-term neurodevelopmental morbidity in term born infants worldwide. Melatonin is a hormone with antioxidant and anti-inflammatory effects that make it a promising molecule for the treatment of perinatal asphyxia. Probably, the synergistic use of hypothermia associated with melatonin treatment may improve the neurological outcome in infants with HIE. In the past 20 years, the efficacy of melatonin in reducing oxidative stress has been demonstrated in animals; however, clinical trials with sufficient sample size of newborns are lacking to date. Since in 2000 we were among the first to study the neuroprotective properties of melatonin on infants, in this review, we want to summarize the advantages and limitations of the investigations conducted to date. KEY POINTS: · HIE is the main cause of morbidity in term born infants worldwide.. · Melatonin is a promising molecule for the treatment of perinatal asphyxia.. · This review summarizes advantages and limitations of the investigations conducted on melatonin..

Pediatric Multisystem Syndrome Associated with SARS-CoV-2 (MIS-C): The Interplay of Oxidative Stress and Inflammation.

Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (MIS-C) is characterized by persistent fever and evidence of single or multiorgan dysfunction, and laboratory evidence of inflammation, elevated neutrophils, reduced lymphocytes, and low albumin. The pathophysiological mechanisms of MIS-C are still unknown. Proinflammatory mediators, including reactive oxygen species and decreased antioxidant enzymes, seems to play a central role. Virus entry activates NOXs and inhibits Nrf-2 antioxidant response inducing free radicals. The biological functions of nonphagocytic NOXs are still under study and appear to include: defense of epithelia, intracellular signaling mechanisms for growth regulation and cell differentiation, and post-translational modifications of proteins. This educational review has the aim of analyzing the newest evidence on the role of oxidative stress (OS) in MIS-C. Only by relating inflammatory mediators to OS evaluation in children following SARS-CoV-2 infection will it be possible to achieve a better understanding of these mechanisms and to reduce long-term morbidity. The link between inflammation and OS is key to developing effective prevention strategies with antioxidants to protect children.

Potential benefits of melatonin to control pain in ventilated preterm newborns: An updated review.

Infants admitted to neonatal intensive care units are repeatedly stimulated by painful events, especially if intubated. Preterm infants are known to have greater pain perception than full term infants due to immaturity of descending inhibitory circuits and poor noxious inhibitory modulation. Newborns exposed to repetitive painful stimuli are at high risk of impairments in brain development and cognition. Chronic pain is induced and supported by proinflammatory cytokines, free radicals, and reactive oxygen species creating a self- sustaining vicious circle. Melatonin is a neurohormone secreted by the pineal gland with antioxidant and anti-inflammatory functions. This review describes the in-depth beneficial effects of melatonin for pain control in ventilated preterm newborns. As yet, a minimal amount of literature has been undertaken to consider all its promising bioactivities. The rationale behind the use of melatonin for pain control has also been taken into account in this review. Besides, this review addresses safety concerns and dosages. The potential benefits of melatonin have been assessed against neurological disorders, respiratory distress, microbial infections, and as analgesic adjuvant during ventilation. Additionally, a possible approach for the use of melatonin in ventilated newborns will be discussed.

Oxidative Stress and Respiratory Diseases in Preterm Newborns.

Premature infants are exposed to increased generation of reactive oxygen species, and on the other hand, they have a deficient antioxidant defense system. Oxidative insult is a salient part of lung injury that begins as acute inflammatory injury in respiratory distress disease and then evolves into chronic and structural scarring leading to bronchopulmonary dysplasia. Oxidative stress is also involved in the pathogenesis of pulmonary hypertension in newborns through the modulation of the vascular tone and the response to pulmonary vasodilators, with consequent decrease in the density of the pulmonary vessels and thickening of the pulmonary arteriolar walls. Oxidative stress has been recognized as both a trigger and an endpoint for several events, including inflammation, hypoxia, hyperoxia, drugs, transfusions, and mechanical ventilation, with impairment of pulmonary function and prolonged lung damage. Redoxomics is the most fascinating new measure to address lung damage due to oxidative stress. The new challenge is to use omics data to discover a set of biomarkers useful in diagnosis, prognosis, and formulating optimal and individualized neonatal care. The aim of this review was to examine the most recent evidence on the relationship between oxidative stress and lung diseases in preterm newborns. What is currently known regarding oxidative stress-related lung injury pathogenesis and the available preventive and therapeutic strategies are also discussed.

Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients.

Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (SMN1) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support SMN improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression.

Ketogenic diet for infants with epilepsy: A literature review.

The ketogenic diet (KD) is an established, nonpharmacological treatment for drug-resistant epilepsy (DRE). Actually, KD and its variants have been shown to be elective and resolute for patients with glucose transporter type 1 (GLUT1) deficiency. The aim of this review was to study the use of KD and its variants in infancy, including the neonatal age, and demonstrate the safety and efficacy of this treatment in patients with the age of 0-23 months affected by DRE already subjected to pharmacological approach attempts. A literature search was conducted using PubMed as the medical database source. We used the age limit of 0-23 months, and we considered only articles published between the years 2015 and 2018, in light of increasing interest worldwide in the use of KD and its variants to manage DRE. We included 52 publications: 1 Cochrane study, 22 retrospective studies, 9 prospective studies, 4 randomized controlled trials (RCTs), 12 clinical cases, and 4 clinical reviews. Literature data showed that KD and its variants are safe and useful in patients with the age of 0-23 months with DRE. Classical KD is of first choice in the treatment of GLUT1 deficiency. Earlier introduction of KD in GLUT1 promises a better outcome and a decrease in seizure frequency in these patients.

A shared protocol for porcine surfactant use in pediatric acute respiratory distress syndrome: a feasibility study.

BACKGROUND: Pediatric ARDS still represents a difficult challenge in Pediatric Intensive Care Units (PICU). Among different treatments proposed, exogenous surfactant showed conflicting results. Aim of this multicenter retrospective observational study was to evaluate whether poractant alfa use in pediatric ARDS might improve gas exchange in children less than 2 years old, according to a shared protocol. METHODS: The study was carried out in fourteen Italian PICUs after dissemination of a standardized protocol for surfactant administration within the Italian PICU network. The protocol provides the administration of surfactant (50 mg/kg) divided in two doses: the first dose is used as a bronchoalveolar lavage while the second as supplementation. Blood gas exchange variations before and after surfactant use were recorded. RESULTS: Sixty-nine children, age 0-24 months, affected by Acute Respiratory Distress Syndrome treated with exogenous porcine surfactant were enrolled. Data collection consisted of patient demographics, respiratory variables and arterial blood gas analysis. The most frequent reasons for PICU admission were acute respiratory failure, mainly bronchiolitis and pneumonia, and septic shock. Fifty-four children (78.3%) had severe ARDS (define by oxygen arterial pressure and inspired oxygen fraction ratio (P/F) < 100), 15 (21.7%) had moderate ARDS (100 < P/F < 200). PO2, P/F, Oxygenation Index (OI) and pH showed a significant improvement after surfactant use with respect to baseline (p < 0.001 at each included time-point for each parameter). No significant difference in blood gas variations were observed among four different subgroups of diseases (bronchiolitis, pneumonia, septic shock and others). Overall, 11 children died (15.9%) and among these, 10 (90.9%) had complex chronic conditions. Two children (18.2%) died while being treated with Extracorporeal Membrane Oxygenation (ECMO). Mortality for severe pARDS was 20.4%. CONCLUSION: The use of porcine Surfactant improves oxygenation, P/F ratio, OI and pH in a population of children with moderate or severe pARDS caused by multiple diseases. A shared protocol seems to be a good option to obtain the same criteria of enrollment among different PICUs and define a unique way of use and administration of the drug for future studies.

High mobility group box 1 and markers of oxidative stress in human cord blood.

BACKGROUND: Parturition induces considerable oxidative stress and many inflammatory mediators, such as high mobility group box 1 (HMGB1), are involved from the beginning of the pregnancy to birth. The aim of the present study was to evaluate serum cord blood concentration of diacron-reactive oxygen metabolites (d-ROM), biological antioxidant potential (BAP), and HMGB1 to investigate the perinatal oxidative status of neonates and correlation with mode of delivery, as well as the influence of labor. METHODS: The subjects consisted of 214 neonates delivered at University Hospital "G. Martino", Messina, in a 6 months period. Venous blood samples were collected from the umbilical cord after cord separation. RESULTS: Umbilical cord venous blood HMGB1 was significantly higher in the spontaneous vaginal delivery (SVD) group than in the elective or emergency cesarean section (CS) group (P = 0.018). Regarding labor, there was no significant difference in HMGB1 concentration in umbilical vein blood between the spontaneous and induced labor groups (P = 0.250). Furthermore, d-ROM was significantly different between the SVD group and the elective or emergency CS group (P = 0.044). BAP concentration, however, was not significantly different, not even with regard to mode of labor. CONCLUSION: Oxidation is higher in newborns delivered by SVD than in those delivered by CS, and HMGB1 may be involved in the mechanisms of birth, and responsible for decidual modifications that lead to birth.

Intrathecal administration of Nusinersen in type 1 SMA: successful psychological program in a single Italian center.

Nusinersen is the first approved drug to treat spinal muscular atrophy (SMA). Its periodic intrathecal delivery may cause psychological burden in infants and in their parents. We report our experience during expanded access program (EAP) for type 1 SMA in a single Italian center. Because of the occurrence of stress emotional states, anxious reactions and fear before, during, and after lumbar puncture (LP), a specific psychological intervention was implemented based on regulation of emotions, anticipatory expectations, and post-event attributions. Activities included the use of fairy tales, distraction, music play through listening preferred cartoon themes in the youngest children, and contextual games and solution of fun riddle quizzes in the oldest ones. State anxiety greatly reduced in children and their parents. Treatment of psychological aspects should therefore become an integral part of health care in SMA infants and children during Nusinersen treatment.

Association between Allergies and Hypercholesterolemia: A Systematic Review.

BACKGROUND: There is controversy in the literature regarding the potential relationship between atopic predisposition (AP) and serum cholesterol levels. To this purpose, we reviewed human studies that investigated this possible link. METHODS: Following PRISMA guidelines, a literature search of PubMed and Science Direct for peer-reviewed journal articles in English from January 2003, with updates through to August 2016, was conducted. Relevant publications were reviewed that included pediatric and adult populations. Information on the study design, sample, intervention, comparators, outcome, time frame, and risk of bias were abstracted for each article. RESULTS: Of 601 reviewed reports, 18 were included in this systematic review. Fifteen studies assessed the relationship between AP and serum cholesterol levels. Due to the lack both of observational and cross-sectional studies from the literature search at this time (only 8 studies also analyzed confounding factors) there is a high possibility of confounding variables (familial and genetic predisposition, age, gender, BMI, comorbidity, and medication status) that could not be ruled out. CONCLUSION: Existing studies are heterogeneous, making it difficult to draw broad conclusions. Future studies and more detailed analyses, considering confounding variables and including a larger and homogeneous population, are needed to strengthen the argument for a link between lipid metabolism and atopy.

Premedication with melatonin vs midazolam: efficacy on anxiety and compliance in paediatric surgical patients.

Preoperative anxiety is a major problem in paediatric surgical patients. Melatonin has been used as a premedicant agent and data regarding effectiveness are controversial. The primary outcome of this randomized clinical trial was to evaluate the effectiveness of oral melatonin premedication, in comparison to midazolam, in reducing preoperative anxiety in children undergoing elective surgery. As secondary outcome, compliance to intravenous induction anaesthesia was assessed. There were 80 children undergoing surgery randomly assigned, 40 per group, to receive oral midazolam (0.5 mg/kg, max 20 mg) or oral melatonin (0.5 mg/kg, max 20 mg). Trait anxiety of children and their mothers (State-Trait Anxiety Inventory) at admission, preoperative anxiety and during anaesthesia induction (Modified Yale Pre-operative Anxiety Scale), and children's compliance with anaesthesia induction (Induction Compliance Checklist) were all assessed. Children premedicated with melatonin and midazolam did not show significant differences in preoperative anxiety levels, either in the preoperative room or during anaesthesia induction. Moreover, compliance during anaesthesia induction was similar in both groups. CONCLUSIONS: This study adds new encouraging data, further supporting the potential use of melatonin premedication in reducing anxiety and improving compliance to induction of anaesthesia in children undergoing surgery. Nevertheless, further larger controlled clinical trials are needed to confirm the real effectiveness of melatonin as a premedicant agent in paediatric population. What is Known: • Although midazolam represents the preferred treatment as a premedication for children before induction of anaesthesia, it has several side effects. • Melatonin has been successfully used as a premedicant agent in adults, while data regarding effectiveness in children are controversial. What is New: • In this study, melatonin was as effective as midazolam in reducing children's anxiety in both preoperative room and at induction of anaesthesia.

Neonatal stridor and laryngeal cyst: Which comes first?

Neonatal stridor is a rare condition usually caused by laryngomalacia. Congenital laryngeal cyst represents an uncommon cause of stridor in the neonatal population and may be misinterpreted as laryngomalacia, leading to serious morbidity and mortality if diagnosis and treatment are delayed. Herein we report the case of a full-term infant with stridor, feeding problems and failure to thrive. Initially, direct laryngoscopy diagnosed only laryngomalacia. As stridor worsened, however, and respiratory distress appeared, repeat laryngoscopy showed vallecular laryngeal cyst, visible macroscopically. The patient was successfully treated with endoscopic marsupialization. There was no evidence of recurrence at follow up after 3 months. This case highlights the importance of laryngoscopic assessment for suspected laryngeal abnormalities in infants with stridor. If symptoms worsen, endoscopy should be repeated, because congenital laryngeal cysts may not be immediately visible macroscopically.

Melatonin Secretion Is Increased in Children with Severe Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Oxidative stress plays a significant role in brain damage and melatonin exhibits both direct and indirect antioxidant effects. The primary aim of the present study was to evaluate serum melatonin levels in children with severe TBI in comparison to critically ill children admitted to the Pediatric Intensive Care Unit for conditions other than TBI. METHODS: Twenty-four children were evaluated, equally divided into severe TBI and no-TBI. Blood samples for serum melatonin analysis were collected at 22:00, 01:00, 03:00, 05:00, 08:00, and 12:00. RESULTS: Mean serum melatonin peaks in children of the TBI group were higher compared to the values of no-TBI critically ill children (495 ± 102 vs. 294 ± 119 pg/mL, p = 0.0002). Furthermore, the difference was even more significant in comparison to values reported in literature for healthy age-matched children (495 ± 102 vs. 197 ± 71 pg/mL, p < 0.0001). CONCLUSION: This study has shown that endogenous serum melatonin levels dramatically increase in children after severe TBI. This elevation is likely to represent a response to oxidative stress and/or inflammation due to severe head injury.

Melatonin Pharmacokinetics Following Oral Administration in Preterm Neonates.

Melatonin possesses potential efficacy in perinatal brain injuries, and has been proposed as adjunctive pharmacological therapy in combination with hypothermia in the clinical setting. However, the pharmacokinetics of melatonin in preterm and term newborns is still unknown. The aim of this study was to analyze the pharmacokinetics of melatonin after intragastric administration in preterm infants. Preterm newborns were enrolled 24-72 h after birth, and randomly assigned to three groups receiving a single bolus of 0.5 mg·kg-1 melatonin, or 3 boluses of 1 or 5 mg·kg-1 of melatonin at 24-h intervals. Blood samples were collected before and at selective times after melatonin administration. The half-life of melatonin in plasma ranged from 7.98 to 10.94 h, and the area under the curve (AUC) from 10.48 to 118.17 µg·mL-1·h-1. Our results indicate a different pharmacokinetic profile in premature newborns, compared to adults and experimental animals. The high peak plasma concentrations and the long half-life indicate that in the neonatal clinical setting, it is possible to obtain and maintain high serum concentrations using a single administration of melatonin repeated every 12/24 h.