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.

Keywords: 6-hydroxymelatonin; cytokines; melatonin; phase I clinical trial; sepsis.

© 2014 The Authors. Journal of Pineal Research Published by John Wiley & Sons Ltd.

Figures

Fig 1

Physiological measures in healthy subjects over 6 hr after receiving an oral dose of melatonin. (A) Heart rate, (B) oxygen saturation, (C) systolic blood pressure, and (D) diastolic blood pressure. Median values shown for clarity, n = 5 subjects per dose cohort. Multilevel linear modeling showed that oxygen saturation and diastolic blood pressure decreased over time, unrelated to dose (P = 0.017 and P < 0.001, respectively), and systolic blood pressure increased with melatonin dose (P < 0.005).

Fig 2

Seum 6-hydroxymelatonin sulfate levels in healthy subjects over 6 hr after an oral dose of melatonin. Median and full range shown, n = 5 per dose cohort. There was a significant effect of dose (P = 0.028), and levels after 30, 50, or 100 mg were significantly higher than after 20 mg (all P < 0.001).

Fig 3

Serum melatonin (red) and serum 6-hydroxymelatonin (blue) in individual subjects following an oral dose of 50 mg melatonin (n = 5 per dose cohort). Lines show median values.

Fig 4

(A) Plasma interleukin-6 (IL-6), (B) IL-10, and (C) lipid hydroperoxide (LPO) from whole blood treated with solvent control (green), lipopolysaccharide and peptidoglycan G (LPS/PepG) plus melatonin (red) or 6-hydroxymelatonin (blue). Median and interquartile range, n = 20 subjects. P-value is Page's trend test. and * = significantly lower than with LPS/PepG alone (Wilcoxon Signed Ranks, P < 0.0001)

Fig 5

Respiratory burst in whole blood treated with solvent control (green), lipopolysaccharide and peptidoglycan G (LPS/PepG) plus melatonin (red) or 6-hydroxymelatonin (blue). Median and interquartile range, n = 20 subjects. P-value is Page's trend test. and * = significantly lower than with LPS/PepG alone (Wilcoxon Signed Ranks, P < 0.0001)