Preterm infants cannot counteract excessive reactive oxygen species (ROS) production due to preterm birth, leading to an excess of lipid peroxidation with malondialdehyde (MDA) production, capable of contributing to brain damage. Melatonin (ME), an endogenous brain hormone, and its metabolites, act as a free radical scavenger against ROS. Unfortunately, preterms have an impaired antioxidant system, resulting in the inability to produce and release ME. This prospective, multicenter, parallel groups, randomized, double-blind, placebo-controlled trial aimed to assess: (i) the endogenous production of ME in very preterm infants (gestational age ≤ 29 + 6 WE, 28 infants in the ME and 26 in the placebo group); (ii) the exogenous hormone availability and its metabolization to the main metabolite, 6-OH-ME after 15 days of ME oral treatment; (iii) difference of MDA plasma concentration, as peroxidation marker, after treatment. Blood was collected before the first administration (T1) and after 15 days of administration (T2). ME and 6-OH-ME were detected by liquid chromatography tandem mass spectrometry, MDA was measured by liquid chromatograph with fluorescence detection. ME and 6-OH-ME were not detectable in the placebo group at any study time-point. ME was absent in the active group at T1. In contrast, after oral administration, ME and 6-OH-ME resulted highly detectable and the difference between concentrations T2 versus T1 was statistically significant, as well as the difference between treated and placebo groups at T2. MDA levels seemed stable during the 15 days of treatment in both groups. Nevertheless, a trend in the percentage of neonates with reduced MDA concentration at T2/T1 was 48.1% in the ME group versus 38.5% in the placebo group. We demonstrated that very preterm infants are not able to produce endogenous detectable plasma levels of ME during their first days of life. Still, following ME oral administration, appreciable amounts of ME and 6-OH-ME were available. The trend of MDA reduction in the active group requires further clinical trials to fix the dosage, the length of ME therapy and to identify more appropriate indexes to demonstrate, at biological and clinical levels, the antioxidant activity and consequent neuroprotectant potential of ME in very preterm newborns.

中文翻译：

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早产儿口服褪黑激素的命运：抗氧化性能和神经保护基础

早产儿无法抵消早产导致的过多活性氧 (ROS) 产生，导致脂质过氧化过多并产生丙二醛 (MDA)，从而导致脑损伤。褪黑素 (ME) 是一种内源性脑激素及其代谢物，可作为 ROS 的自由基清除剂。不幸的是，早产儿的抗氧化系统受损，导致无法产生和释放 ME。这项前瞻性、多中心、平行组、随机、双盲、安慰剂对照试验旨在评估：(i) 极早产儿（胎龄 ≤ 29 + 6 WE，28 名 ME 婴儿和 26 名婴儿）中 ME 的内源性产生。安慰剂组）；(ii) ME口服治疗15天后外源激素的有效性及其代谢为主要代谢物6-OH-ME；(iii) 治疗后作为过氧化标志物的MDA血浆浓度的差异。在第一次给药前（T1）和给药15天后（T2）采集血液。ME和6-OH-ME采用液相色谱串联质谱法测定，MDA采用液相色谱荧光检测法测定。在任何研究时间点，安慰剂组均未检测到 ME 和 6-OH-ME。T1 时活跃组中不存在 ME。相比之下，口服给药后，ME 和 6-OH-ME 的结果高度可检测，T2 与 T1 浓度之间的差异具有统计学显着性，T2 时治疗组和安慰剂组之间的差异也具有统计学显着性。在 15 天的治疗期间，两组的 MDA 水平似乎都很稳定。尽管如此，ME 组中 T2/T1 时 MDA 浓度降低的新生儿百分比趋势为 48.1%，而安慰剂组为 38.5%。我们证明，极早产儿在出生后的第一天无法产生内源性可检测的血浆 ME 水平。尽管如此，口服 ME 后，仍可得到相当量的 ME 和 6-OH-ME。活性组MDA减少的趋势需要进一步的临床试验来确定ME治疗的剂量、持续时间，并确定更合适的指标，以在生物学和临床水平上证明ME对极早产儿的抗氧化活性和随之而来的神经保护潜力新生儿。