title: Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis.
abstract: Sepsis is a massive inflammatory response mediated by infection, characterized by oxidative stress, release of cytokines, and mitochondrial dysfunction. Melatonin accumulates in mitochondria, and both it and its metabolites have potent antioxidant and anti-inflammatory activities and may be useful in sepsis. We undertook a phase I dose escalation study in healthy volunteers to assess the tolerability and pharmacokinetics of 20, 30, 50, and 100 mg oral doses of melatonin. In addition, we developed an ex vivo whole blood model under conditions mimicking sepsis to determine the bioactivity of melatonin and the major metabolite 6-hydroxymelatonin at relevant concentrations. For the phase I trial, oral melatonin was given to five subjects in each dose cohort (n = 20). Blood and urine were collected for measurement of melatonin and 6-hydroxymelatonin, and symptoms and physiological measures were assessed. Validated sleep scales were completed. No adverse effects after oral melatonin, other than mild transient drowsiness with no effects on sleeping patterns, were seen, and no symptoms were reported. Melatonin was rapidly cleared at all doses with a median [range] elimination half-life of 51.7 [29.5-63.2] min across all doses. There was considerable variability in maximum melatonin levels within each dose cohort, but 6-hydoxymelatonin sulfate levels were less variable and remained stable for several hours. For the ex vivo study, blood from 20 volunteers was treated with lipopolysaccharide and peptidoglycan plus a range of concentrations of melatonin/6-hydroxymelatonin. Both melatonin and 6-hydroxymelatonin had beneficial effects on sepsis-induced mitochondrial dysfunction, oxidative stress, and cytokine responses at concentrations similar to those achieved in vivo.
authors.affiliation: Division of Applied Health, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK; Intensive Care Unit, Aberdeen Royal Infirmary, Aberdeen, UK.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Galley
authors.forename: Damon A
authors.initials: DA
authors.lastname: Lowes
authors.forename: Lee
authors.initials: L
authors.lastname: Allen
authors.forename: Gary
authors.initials: G
authors.lastname: Cameron
authors.forename: Lorna S
authors.initials: LS
authors.lastname: Aucott
authors.forename: Nigel R
authors.initials: NR
authors.lastname: Webster
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage / Q000493:pharmacokinetics; D016207:Cytokines / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008550:Melatonin / Q000008:administration & dosage / Q000493:pharmacokinetics; D018384:Oxidative Stress / Q000187:drug effects*; D018805:Sepsis / Q000097:blood* / Q000188:drug therapy*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D008550:Melatonin
keywords: 6-hydroxymelatonin; cytokines; melatonin; phase I clinical trial; sepsis