Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis.
Study Goal
The researchers aimed to assess the tolerability, pharmacokinetics, and bioactivity of melatonin and its metabolite 6-hydroxymelatonin in healthy volunteers and an ex vivo sepsis model.
Results Summary
Oral melatonin was well-tolerated with no significant adverse effects, and both melatonin and 6-hydroxymelatonin showed beneficial effects on sepsis-induced mitochondrial dysfunction, oxidative stress, and cytokine responses at concentrations achievable in vivo.
Population
Healthy volunteers (n=20) and ex vivo blood samples from 20 volunteers.
Effective Dosage
20, 30, 50, and 100 mg oral doses.
Duration
Not specified (single-dose study).
Interactions
None mentioned.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
oral melatonin | no change | adverse effects | healthy volunteers | null | No adverse effects | #1 |
oral melatonin | increase | drowsiness | healthy volunteers | null | mild transient drowsiness | #2 |
oral melatonin | no change | sleeping patterns | healthy volunteers | null | no effects | #3 |
melatonin | decrease | elimination half-life | healthy volunteers | 51.7 [29.5-63.2] min | rapidly cleared | #4 |
melatonin | null | maximum melatonin levels | healthy volunteers | null | considerable variability | #5 |
6-hydroxymelatonin sulfate | no change | levels | healthy volunteers | for several hours | less variable and remained stable | #6 |
melatonin | decrease | sepsis-induced mitochondrial dysfunction | ex vivo whole blood model | null | had beneficial effects | #7 |
melatonin | decrease | oxidative stress | ex vivo whole blood model | null | had beneficial effects | #8 |
melatonin | decrease | cytokine responses | ex vivo whole blood model | null | had beneficial effects | #9 |
6-hydroxymelatonin | decrease | sepsis-induced mitochondrial dysfunction | ex vivo whole blood model | null | had beneficial effects | #10 |
6-hydroxymelatonin | decrease | oxidative stress | ex vivo whole blood model | null | had beneficial effects | #11 |
6-hydroxymelatonin | decrease | cytokine responses | ex vivo whole blood model | null | had beneficial effects | #12 |
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.