Journal of pineal research
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Multicenter Study
Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis.
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. ⋯ 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.