Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study

Robertson, Nicola J.; Martinello, Kathryn; Lingam, Ingran; Avdic-Belltheus, Adnan; Meehan, Christopher; Alonso-Alconada, Daniel; Ragab, Sara; Bainbridge, Alan; Sokolska, Magdalena; Tachrount, Mohamed; Middleton, Benita; Price, David L.; Hristova, Mariya; Golay, Xavier; Raschini, Annamaria Soliani; Aquino, Giancarlo; Pelizzi, Nicola; Facchinetti, Fabrizio

doi:10.1016/j.nbd.2018.10.004

Cited by 47 publications

(82 citation statements)

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“…Further adjustments to HT protocols do not improve outcome 6,7 , therefore adjunct therapies to augment HT protection are urgently needed.Pre-clinical studies suggest that melatonin (N-acetyl-5-methoxytryptamine) in pharmacologic levels is safe and neuroprotective for hypoxic-ischemic injury in the adult 8 and neonatal 9 brain, mediated by anti-oxidant, anti-apoptotic and anti-inflammatory properties 10,11 . Extrapolating from in vitro 12 and pre-clinical piglet studies 13,14 showing melatonin reduces cell death in a concentration-dependent manner, we deduce that a plasma www.nature.com/scientificreports www.nature.com/scientificreports/ transient cerebral hypoxia ischemia. Compared to the original studies based on assessment of NTP reduction during HI on 31 P MRS 29 , the monitoring and titration of the HI insult were modified recently in this and other studies 30 .…”

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confidence: 85%

“…In a previous piglet study, we observed augmentation of HT protection with 30 mg/kg/24 h melatonin with ethanol excipient when started 10 mins after hypoxia-ischemia (HI), reaching blood levels >15 mg/l within 1 h 13 . In a subsequent study using a proprietary melatonin formulation (15 mg/kg), without ethanol excipient, given 2-8 h after HI, there was less clear protection with therapeutic levels reached only at 8 h 14 . In this same study, no protection was seen with 5 mg/kg melatonin started at 2 h (blood melatonin <4 mg/l) 14 .…”

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confidence: 94%

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High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

Robertson

Lingam

Meehan

et al. 2020

Sci Rep

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With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study's objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1-13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1-13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (Ht+V; n = 7); (iii) HT + Melatonin (Ht+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after Hi. comparing Ht+M to HT, aEEG scores recovered more quickly by 19 h (p < 0.05); comparing HT+V to HT, aEEG recovered from 31 h (p < 0.05). Brain phosphocreatine/inorganic phosphate and NTP/ exchangeable phosphate were higher at 48 h in HT+M versus Ht (p = 0.036, p = 0.049 respectively). Including both 24 h and 48 h measurements, the rise in Lactate/N-acetyl aspartate was reduced in white (p = 0.030) and grey matter (p = 0.038) after HI. Reduced overall TUNEL positive cells were observed in Ht+M (47.1 cells/mm 2 ) compared to HT (123.8 cells/mm 2 ) (p = 0.0003) and HT+V (97.5 cells/mm 2 ) compared to Ht (p = 0.012). Localized protection was seen in white matter for HT+M versus Ht (p = 0.036) and internal capsule for HT+M compared to Ht (p = 0.001) and HT+V versus Ht (p = 0.006). Therapeutic melatonin levels (15-30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective.Intrapartum-related neonatal encephalopathy (NE) is a major healthcare problem. Worldwide in 2010, NE accounted for 287,000 deaths and 400,000 survivors with impairment 1 . NE cannot be prevented in most cases and therapies are limited. The incidence of NE in Western Europe is 1-3/1000 term births and in low-and mid-resource settings the incidence is ~10 times higher 1,2 . Over the last 2 decades, in settings with neonatal intensive care facilities, therapeutic hypothermia (HT) is routinely used for moderate-to-severe NE, improving survival and reducing disability 3 . However, although the severity of cerebral palsy has reduced with HT 4 , survivors have significantly lower cognitive scores which are on average 14 IQ points lower than matched peers even in the absence of cerebral palsy at school-age 5 . Further adjustments to HT protocols do not improve outcome 6,7 , therefore adjunct therapies to augment HT protection are urgently needed.Pre-clinical studies suggest that melatonin (N-acetyl-5-methoxytryptamine) in pharmacologic levels is safe and neuroprotective for hypoxic-ischemic injury in the adult 8 and neonatal 9 brain, mediated by anti-oxidant, anti-apoptotic and anti-inflammatory properties 10,11 . Ex...

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confidence: 85%

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confidence: 94%

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

Robertson

Lingam

Meehan

et al. 2020

Sci Rep

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“…Blood samples (1 mL) were collected from an indwelling arterial catheter immediately before (time 0) and 1, 3, | 3 of 11 BALDUINI et AL. 6,12,24,48, and 96 hours after starting the melatonin infusion. Blood samples were collected in blood collection tubes containing lithium heparin (cat #367884; BD Vacutainer ® , Franklin Lakes, NJ, USA) and stored at 4°C until centrifugation.…”

Section: Dose and Medicationmentioning

confidence: 99%

“…Preclinical studies have shown that melatonin improves hypothermia efficacy . Melatonin is a naturally occurring substance mainly produced from the pineal gland and well known for its role in regulating the circadian rhythm.…”

Section: Introductionmentioning

confidence: 99%

“…Preclinical studies have shown that melatonin improves hypothermia efficacy. [4][5][6] Melatonin is a naturally occurring substance mainly produced from the pineal gland and well known for its role in regulating the circadian rhythm. However, Melatonin also possesses pleiotropic effects including free radical scavenger activity and stimulation of anti-oxidant enzymes.…”

Section: Introductionmentioning

confidence: 99%

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Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia

Balduini

Weiss

Carloni

et al. 2019

Journal of Pineal Research

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Introduction Neonates with hypoxic‐ischemic encephalopathy (HIE) undergoing hypothermia may benefit from adjunctive therapy with melatonin. However, melatonin safety, pharmacokinetics (PK), and dosage in this sensitive population are still unknown. Methods and results This study assessed the PK and safety of melatonin enteral administration to neonates with HIE undergoing hypothermia. Melatonin was infused at 0.5 mg/kg in five neonates with HIE undergoing hypothermia. Infusion started 1 hour after the neonates reached the target temperature of 33.5°C. Blood samples were collected before and at selective times after melatonin infusion. Abdominal complications or clinically significant changes in patients’ vital signs were not found during or after melatonin. The peak plasma concentration reached 0.25 µg/mL. The area under the curve in 24 hours was 4.35 µg/mL*h. Discussion Melatonin half‐life and clearance were prolonged, and the distribution volume decreased compared to adults. In silico simulation estimated that the steady state can be reached after four infusions. Hypothermia does not affect melatonin PK. In humans high blood concentrations with lower doses can be achieved compared to animal experimentation, although intravenous administration is advised in the neonate population. Our study is a preparatory step for future clinical studies aimed at assessing melatonin efficacy in HIE.

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Melatonin treatment for newborns with hypoxic ischaemic encephalopathy

Hurley

O’Dea

Aslam

et al. 2020

Cochrane Database of Systematic Reviews

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Melatonin as an adjunct to therapeutic hypothermia in a piglet model of neonatal encephalopathy: A translational study

Cited by 47 publications

References 58 publications

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia

Melatonin treatment for newborns with hypoxic ischaemic encephalopathy

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