The imbalance between pro-oxidant and antioxidant forces causes oxidative insults. Any augmented oxygen use increases the rate of production of reactive oxygen species that damages cells, especially those in development. Free radicals and the associated molecular damage are very likely critical components of several diseases of newborns. Melatonin, an endogenously produced indolamine in adult humans, but only minimally so in neonates, is a highly effective antioxidant and free radical scavenger, as demonstrated in vitro, in animal and in human studies. Melatonin detoxifies reactive species via electron donation. In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant: this molecule and its metabolites efficiently upregulates antioxidant enzymes (including glutathione peroxidases and glutathione reductase), and down regulates pro-oxidant enzymes (nitric oxide synthases and lipoxygenases). Therefore, melatonin is an attractive agent in the treatment of “Oxidative stress related diseases” of the newborn. In newborn humans, melatonin has been used at doses ranging from 0.1 to 100 mg/Kg; however, due to the lack of pharmacokinetic data in neonates, it is difficult to establish a therapeutic effective dose. Recent investigations on the pharmacokinetic on newborns, reported that after administration of melatonin, in a single bolus of 0.5 mg/Kg, by intragastric administration, resulted in higher serum melatonin level than adults. Such findings suggest that is possible to obtain and maintain therapeutic concentrations with this dose. However, no data were available on the therapeutic efficacy of these specific doses. The aim of the present study is to investigate the effects of oral administration of melatonin on oxidative stress biomarkers in premature neonates. Therefore 0.5 mg/Kg/die of melatonin has been administrated orally to 35 preterm infants with gestational age <34 weeks, for the first week of life in comparison to placebo. Serum levels of oxidative stress biomarkers (F2 Isoprostanes, Advanced Oxidative Protein Products, Non-Protein Bound Iron) and serum melatonin were assessed at baseline T0 (0-2h of life), T1 (24h), T2 (72h). We found no significant reduction in serum levels of oxidative stress biomarkers, except for F2 Isoprostanes at T1, which remains of unclear relevance. Analyzing serum melatonin levels, as expected, we found a significant increase from baseline T0 to T1 and T2 in the group receiving melatonin. However, endogenous melatonin levels increased also in the placebo group, and this result may be considered a response to counteract the elevated oxidative stress associated with the preterm birth. We also found that, despite the fact that melatonin was administered based on the weight of the newborn, serum melatonin levels were dependent on the total amount of melatonin administered rather than related to the ratio melatonin/weight. The data obtained indicate that studies with more preterm infants are needed to verify the efficacy of the antioxidant effect of melatonin and a higher, fixed dose, instead of a weight based dosage, is required to have a clearer therapeutic efficacy.

Antioxidant treatment in neonatal population

D'ANGELO, GABRIELLA
2020

Abstract

The imbalance between pro-oxidant and antioxidant forces causes oxidative insults. Any augmented oxygen use increases the rate of production of reactive oxygen species that damages cells, especially those in development. Free radicals and the associated molecular damage are very likely critical components of several diseases of newborns. Melatonin, an endogenously produced indolamine in adult humans, but only minimally so in neonates, is a highly effective antioxidant and free radical scavenger, as demonstrated in vitro, in animal and in human studies. Melatonin detoxifies reactive species via electron donation. In the last several years, hundreds of publications have confirmed that melatonin is a broad-spectrum antioxidant: this molecule and its metabolites efficiently upregulates antioxidant enzymes (including glutathione peroxidases and glutathione reductase), and down regulates pro-oxidant enzymes (nitric oxide synthases and lipoxygenases). Therefore, melatonin is an attractive agent in the treatment of “Oxidative stress related diseases” of the newborn. In newborn humans, melatonin has been used at doses ranging from 0.1 to 100 mg/Kg; however, due to the lack of pharmacokinetic data in neonates, it is difficult to establish a therapeutic effective dose. Recent investigations on the pharmacokinetic on newborns, reported that after administration of melatonin, in a single bolus of 0.5 mg/Kg, by intragastric administration, resulted in higher serum melatonin level than adults. Such findings suggest that is possible to obtain and maintain therapeutic concentrations with this dose. However, no data were available on the therapeutic efficacy of these specific doses. The aim of the present study is to investigate the effects of oral administration of melatonin on oxidative stress biomarkers in premature neonates. Therefore 0.5 mg/Kg/die of melatonin has been administrated orally to 35 preterm infants with gestational age <34 weeks, for the first week of life in comparison to placebo. Serum levels of oxidative stress biomarkers (F2 Isoprostanes, Advanced Oxidative Protein Products, Non-Protein Bound Iron) and serum melatonin were assessed at baseline T0 (0-2h of life), T1 (24h), T2 (72h). We found no significant reduction in serum levels of oxidative stress biomarkers, except for F2 Isoprostanes at T1, which remains of unclear relevance. Analyzing serum melatonin levels, as expected, we found a significant increase from baseline T0 to T1 and T2 in the group receiving melatonin. However, endogenous melatonin levels increased also in the placebo group, and this result may be considered a response to counteract the elevated oxidative stress associated with the preterm birth. We also found that, despite the fact that melatonin was administered based on the weight of the newborn, serum melatonin levels were dependent on the total amount of melatonin administered rather than related to the ratio melatonin/weight. The data obtained indicate that studies with more preterm infants are needed to verify the efficacy of the antioxidant effect of melatonin and a higher, fixed dose, instead of a weight based dosage, is required to have a clearer therapeutic efficacy.
File in questo prodotto:
File Dimensione Formato  
Tesi Dottorato Gabriella D'Angelo.pdf

accesso aperto

Descrizione: Tesi di dottorato
Tipologia: Tesi di dottorato
Licenza: Creative commons
Dimensione 650.72 kB
Formato Adobe PDF
650.72 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/3169690
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact