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

Autor: Robertson NJ; University College London, London WC1E 6HX, UK; Division of Neonatology, Department of Pediatrics, Sidra Medicine, Doha, Qatar. Electronic address: n.robertson@ucl.ac.uk., Martinello K; University College London, London WC1E 6HX, UK., Lingam I; University College London, London WC1E 6HX, UK., Avdic-Belltheus A; University College London, London WC1E 6HX, UK., Meehan C; University College London, London WC1E 6HX, UK., Alonso-Alconada D; University of the Basque Country, Leioa, Spain., Ragab S; University College London, London WC1E 6HX, UK., Bainbridge A; University College London Hospitals NHS Trust, UK., Sokolska M; University College London Hospitals NHS Trust, UK., Tachrount M; Chronobiology Group, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK., Middleton B; Chronobiology Group, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK., Price D; University College London Hospitals NHS Trust, UK., Hristova M; University College London, London WC1E 6HX, UK., Golay X; Institute of Neurology, Queen Square, University College London, London, UK., Soliani Raschini A; Chiesi Farmaceutici S.p.A., Parma, Italy., Aquino G; Chiesi Farmaceutici S.p.A., Parma, Italy., Pelizzi N; Chiesi Farmaceutici S.p.A., Parma, Italy., Facchinetti F; Chiesi Farmaceutici S.p.A., Parma, Italy.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2019 Jan; Vol. 121, pp. 240-251. Date of Electronic Publication: 2018 Oct 06.
DOI: 10.1016/j.nbd.2018.10.004
Abstrakt: Therapeutic hypothermia is only partially protective for neonatal encephalopathy; there is an urgent need to develop treatments that augment cooling. Our objective was to assess safety, efficacy and pharmacokinetics of 5 and 15 mg/kg/24 h melatonin (proprietary formulation) administered at 2 h and 26 h after hypoxia-ischemia (HI) with cooling in a piglet model. Following moderate cerebral HI, 30 piglets were eligible and randomized to: i) Hypothermia (33.5 °C, 2-26 h) and vehicle (HT + V;n = 13); b) HT and 5 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-5;n = 4); c) HT and 15 mg/kg melatonin over 6 h at 2 h and 26 h after HI (HT + Mel-15;n = 13). Intensive care was maintained for 48 h; brain MRS was acquired and cell death (TUNEL) evaluated at 48 h. Comparing HT + V with HT + Mel-5 and HT + Mel-15, there was no difference in blood pressure or inotropic support needed, brain Lactate/N Acetylaspartate at 24 h and 48 h was similar, ATP/phosphate pool was higher for HT + Mel-15 versus HT + V at 24 h (p = 0.038) but not 48 h. A localized reduction in TUNEL positive cell death was observed in the sensorimotor cortex in the 15 mg/kg melatonin group (HT + Mel-15 versus HT + V; p < 0.003) but not in the 5 mg/kg melatonin group (HT + Mel-5 versus HT + V; p = 0.808). Putative therapeutic melatonin levels were reached 8 h after HI (10 4 increase from baseline; ~15-30 mg/l). Mean ± SD peak plasma melatonin levels after the first infusion were 0.0014 ± 0.0012 mg/l in the HT + V group, 3.97 ± 1.53 mg/l in the HT + Mel-5 group and 16.8 ± 8.3 mg/l in the HT + Mel-15 group. Protection was dose dependent; 15 mg/kg melatonin started 2 h after HI, given over 6 h, was well tolerated and augmented hypothermic protection in sensorimotor cortex. Earlier attainment of therapeutic plasma melatonin levels may optimize protection by targeting initial events of reperfusion injury. The time window for intervention with melatonin, as adjunct therapy with cooling, is likely to be narrow and should be considered in designing future clinical studies.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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