Antioxidant therapy targeted at mitochondria has the potential to reduce inflammation,
mitochondrial damage and organ dysfunction in sepsis. Melatonin accumulates in mitochondria
and both it and its metabolites have potent antioxidant and anti-inflammatory activity,
preventing organ dysfunction in a rat model of sepsis. The investigators propose a study in
healthy volunteers to assess the tolerability and pharmacokinetics of exogenous melatonin and
its major metabolites and to relate these doses to ex vivo anti-inflammatory and antioxidant
activities. Groups of healthy subjects will receive increasing sequential doses of oral
melatonin in an open label dose escalation study. Ex vivo inflammatory responses, oxidative
stress and mitochondrial function at concentrations of melatonin identified in the dose
escalation study will be determined following exposure of whole blood to an inflammatory
insult. This will provide crucial information to inform a subsequent phase II clinical trial
of melatonin in patients with sepsis.