Oral Substitution of Melatonin in Critical Care: A Pharmacokinetic Study in Patients with Intracranial Hemorrhage

  • Mohammadreza Rouini 1Biopharmaceutics Division, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Niloofar Khoshnam Rad Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Mojtaba Mojtahedzadeh 2Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Atabak Najafi 3Department of Anesthesiology and Critical Care, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
  • Hamidreza Sharifnia 3Department of Anesthesiology and Critical Care, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
  • Mehrnoush Dianatkhah 2Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Farhad Najmeddin 2Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
  • Ali Mohammad Hadi 4Departmant of Clinical Pharmacy, College of Pharmacy, University of Basrah , Basrah, Iraq.
  • Bita Shahrami 2Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Melatonin, ICH, Pharmacokinetics, HPLC



Intracerebral hemorrhage (ICH) is a devastating condition with a high mortality and morbidity rate. Neuroprotective agents protect surrounding brain tissue from the toxic effects of hematoma and can result in better outcomes. There is evidence demonstrating the neuroprotective benefits of melatonin in experimental animal models of ICH. Reduced melatonin levels have been reported in the intensive care unit (ICU) patients. The aim of this study was to evaluate baseline melatonin levels and pharmacokinetic profile of melatonin in ICH patients.


24  patients with non-traumatic ICH were divided into melatonin and control groups. Subjects in the melatonin group received 30 mg of melatonin for 5 days. Another group of 12 healthy volunteers also were recruited for the study. Baseline serum melatonin levels were measured for all groups. For the pharmacokinetic study, sampling intervals were 0.25, 0.5, 0.75, 1.5, 3, 6 and 10 hours after melatonin administration. Samples were analyzed using an HPLC system with fluorescence detection.


Serum melatonin concentrations found to be decreased in all patients. Patients showed a significant increase in levels by the third day but still lower than healthy volunteers. By day 5, the melatonin group reaches melatonin levels, statistically similar to healthy volunteers, but the control group didn't reach normal levels even on the seventh day of study.


Our study suggests that monitoring melatonin levels and supplementing with exogenous melatonin can correct the reduced levels. Further studies focused on melatonin administration in ICH patients can be helpful in evaluating clinical outcomes in these patients.


1. Castellanos M, Freijo MM, Fernández JCL, Nombela F, Simal P, Castillo J, et al. Clinical practice guidelines in intracerebral haemorrhage. 2013;28(4):236–49.
2. Dastur CK, Yu W. Current management of spontaneous intracerebral haemorrhage. Bmj [Internet]. 2017;2(1):21–9. Available from: http://svn.bmj.com/cgi/doi/10.1136/svn-2016-000047
3. Hemphill JC, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Vol. 46, Stroke. 2015. 2032-2060 p.
4. Hwang BY, Appelboom G, Ayer A, Kellner CP, Kotchetkov IS, Gigante PR, et al. Advances in neuroprotective strategies: Potential therapies for intracerebral hemorrhage. Cerebrovasc Dis. 2011;31(3):211–22.
5. Gonzales-Portillo GS, Lozano D, Aguirre D, Reyes S, Borlongan C V, Tajiri N, et al. An update on the use of melatonin as a stroke therapeutic. Minerva Med [Internet]. 2015;106(3):169–75. Available from: https://login.e.bibl.liu.se/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=cmedm&AN=25000217&site=eds-live&scope=site
6. Andrabi SS, Parvez S, Tabassum H. Melatonin and ischemic stroke: Mechanistic roles and action. Adv Pharmacol Sci. 2015;2015.
7. Wu HJ, Wu C, Niu HJ, Wang K, Mo LJ, Shao AW, et al. Neuroprotective Mechanisms of Melatonin in Hemorrhagic Stroke. Cell Mol Neurobiol. 2017;37(7):1173–85.
8. Mistraletti G, Sabbatini G, Taverna M, Figini MA, Umbrello M, Magni P, et al. Pharmacokinetics of orally administered melatonin in critically ill patients. J Pineal Res. 2010;48(2):142–7.
9. Miyazaki T, Kuwano H, Kato H, Ando H, Kimura H, Inose T, et al. Correlation between serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagectomy. Surgery. 2003;133(6):662–8.
10. Perras B, Kurowski V, Dodt C. Nocturnal melatonin concentration is correlated with illness severity in patients with septic disease [13]. Intensive Care Med. 2006;32(4):624–5.
11. Shekleton JA, Parcell DL, Redman JR et al. Sleep disturbance and melatonin levels following traumatic brain injury. Neurology. 2010;74(334002):1732–8.
12. Shilo L, Dagan Y, Smorjik Y, Weinberg U, Dolev S, Komptel B, et al. Patients in the intensive care unit suffer from severe lack of sleep associated with loss of normal melatonin secretion pattern. Am J Med Sci [Internet]. 1999;317(5):278–81. Available from: http://dx.doi.org/10.1016/S0002-9629(15)40528-2
13. FRISK U, OLSSON J, NYLÉN P, HAHN RG. Low melatonin excretion during mechanical ventilation in the intensive care unit. Clin Sci [Internet]. 2004;107(1):47–53. Available from: http://clinsci.org/lookup/doi/10.1042/CS20030374
14. Olofsson K, Alling C, Lundberg D, Malmros C. Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand. 2004;48(6):679–84.
15. Seifman MA, Gomes K, Nguyen PN, Bailey M, Rosenfeld J V., Cooper DJ, et al. Measurement of serum melatonin in intensive care unit patients: Changes in traumatic brain injury, trauma and medical conditions. Front Neurol. 2014;5(NOV):1–7.
16. Agha A, Rogers B, Mylotte D, Taleb F, Tormey W, Phillips J, et al. Neuroendocrine dysfunction in the acute phase of traumatic brain injury. Clin Endocrinol (Oxf). 2004;60(5):584–91.
17. Domínguez-Rodríguez A, Abreu-González P, García MJ, Sanchez J, Marrero F, de Armas-Trujillo D. Decreased nocturnal melatonin levels during acute myocardial infarction. J Pineal Res [Internet]. 2002;33(4):248–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12390508
18. Bonnefont-Rousselot D, Collin F. Melatonin: Action as antioxidant and potential applications in human disease and aging. Toxicology [Internet]. 2010;278(1):55–67. Available from: http://dx.doi.org/10.1016/j.tox.2010.04.008
19. Gutteridge JM, Mitchell J. Redox imbalance in the critically ill. Br Med Bull. 1999;55(1):49–75.
20. Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med [Internet]. 2005;31(3):327–37. Available from: http://link.springer.com/10.1007/s00134-004-2522-z
21. Lovat R, Preiser J-C. Antioxidant therapy in intensive care. Curr Opin Crit Care [Internet]. 2003;9(4):266–70. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00075198-200308000-00003
22. Shilo L, Dagan Y, Smorjik Y, Weinberg U, Dolev S, Komptel B, et al. Effect of Melatonin on Sleep Quality of Copd Intensive Care Patients: a Pilot Study. Chronobiol Int [Internet]. 2000;17(1):71–6. Available from: http://www.tandfonline.com/action/journalInformation?journalCode=icbi20%5Cnhttp://dx.doi.org/10.1081/CBI-100101033%5Cnhttp://www.tandfonline.com/doi/full/10.1081/CBI-100101033
23. Ibrahim MG, Bellomo R, Hart GK, Norman TR, Goldsmith D, Bates S, et al. A double-blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomised patients. Crit Care Resusc. 2006;8(3):187–91.
24. Bellapart J, Boots R. Potential use of melatonin in sleep and delirium in the critically ill. Br J Anaesth. 2012;108(4):572–80.
25. Mistraletti G, Paroni R, Umbrello M, D’Amato L, Sabbatini G, Taverna M, et al. Melatonin pharmacological blood levels increase total antioxidant capacity in critically ill patients. Int J Mol Sci. 2017;18(4).
26. Bellapart J, Roberts JA, Appadurai V, Wallis SC, Nuñez-Nuñez M, Boots RJ. Pharmacokinetics of a novel dosing regimen of oral melatonin in critically ill patients. Clin Chem Lab Med. 2016;54(3):467–72.
27. Harpsøe NG, Andersen LPH, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: A systematic review. Eur J Clin Pharmacol. 2015;71(8):901–9.
28. Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care [Internet]. 2008;12(2):R52. Available from: http://ccforum.biomedcentral.com/articles/10.1186/cc6871
29. J. Claude Hemphill III, MD; David C. Bonovich, MD; Lavrentios Besmertis, MD; Geoffrey T. Manley, MD, PhD; S. Claiborne Johnston, MD M. The ICH Score. Stroke. 2001;32:891–7.
30. Center for Drug Evaluation and Research. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. US Dep Heal Hum Serv [Internet]. 2005;(July):1–27. Available from: http://www.fda.gov/downloads/Drugs/Guidance/UCM078932.pdf
31. Department of Health and Aging - Therapeutic Goods Administration. Australian Public Assessment Report for Tocilizumab Proprietary Product Name : Actemra Sponsor : Roche Products Pty Ltd. 2013;(December). Available from: https://www.tga.gov.au/sites/default/files/auspar-vismodegib-130913.pdf
32. Ueda Y, Masuda T, Ishida A, Misumi S, Shimizu Y, Jung CG, et al. Enhanced electrical responsiveness in the cerebral cortex with oral melatonin administration after a small hemorrhage near the internal capsule in rats. J Neurosci Res. 2014;92(11):1499–508.
33. Nair A, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm [Internet]. 2016;7(2):27. Available from: http://www.jbclinpharm.org/text.asp?2016/7/2/27/177703
34. Muñoz JLP, Ceinos RM, Soengas JL, Míguez JM. A simple and sensitive method for determination of melatonin in plasma, bile and intestinal tissues by high performance liquid chromatography with fluorescence detection. J Chromatogr B Anal Technol Biomed Life Sci. 2009;877(22):2173–7.
35. Karasek M, Winczyk K. Melatonin in humans. J Physiol Pharmacol. 2006;57(5):19–39.
36. Powers WJ. Intracerebral hemorrhage and head trauma: Common effects and common mechanisms of injury. Stroke. 2010;41(10 SUPPL. 1):107–11.
37. Kilic U, Yilmaz B, Ugur M, Yüksel A, Reiter RJ, Hermann DM, et al. Evidence that membrane-bound G protein-coupled melatonin receptors MT1 and MT2 are not involved in the neuroprotective effects of melatonin in focal cerebral ischemia. J Pineal Res. 2012;52(2):228–35.
38. De Almeida EA, Di Mascio P, Harumi T, Spence DW, Moscovitch A, Hardeland R, et al. Measurement of melatonin in body fluids: Standards, protocols and procedures. Child’s Nerv Syst. 2011;27(6):879–91.
39. Boucher BA, Wood GC, Swanson JM. Pharmacokinetic Changes in Critical Illness. Crit Care Clin. 2006;22(2):255–71.
40. Andersen LPH, Gögenur I, Rosenberg J, Reiter RJ. Pharmacokinetics of Melatonin: The Missing Link in Clinical Efficacy? Clin Pharmacokinet. 2016;55(9):1027–30.
41. DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino JS. The absolute bioavailability of oral melatonin. J Clin Pharmacol [Internet]. 2000;40(7):781–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10883420
42. Zhdanova I V., Wurtman RJ, Balcioglu A, Kartashov AI, Lynch HJ. Endogenous melatonin levels and the fate of exogenous melatonin: Age effects. Journals Gerontol Ser A Biol Sci Med Sci. 1998;53A(4):B293–8.
43. Mallo C, Zaidan R, Galy G, Vermeulen E, Brun J, Chazot G, et al. Pharmacokinetics of melatonin in man after intravenous infusion and bolus injection. Eur J Clin Pharmacol. 1990;38(3):297–301.
44. Härtter S, Nordmark A, Rose DM, Bertilsson L, Tybring G, Laine K. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYPIA2 activity. Br J Clin Pharmacol. 2003;56(6):679–82.
45. Fourtillan JB, Brisson AM, Gobin P, Ingrand I, Decourt JP, Girault J. Bioavailability of melatonin in humans after day-time administration of D7melatonin. Biopharm Drug Dispos. 2000;21(1):15–22.
46. Shirakawa S, Tsuchiya S, Tsutsumi Y, Kotorii T, Uchimura N, Sakamoto T, et al. Time course of saliva and serum melatonin levels after ingestion of melatonin. Psychiatry Clin Neurosci [Internet]. 1998;52(2):266–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9628188
How to Cite
Rouini M, Khoshnam Rad N, Mojtahedzadeh M, Najafi A, Sharifnia H, Dianatkhah M, Najmeddin F, Mohammad Hadi A, Shahrami B. Oral Substitution of Melatonin in Critical Care: A Pharmacokinetic Study in Patients with Intracranial Hemorrhage. J Pharm Care. 8(1):3-10.
Original Article(s)