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 Mail 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.
Keywords:
Melatonin, Intracranial Hemorrhage, Pharmacokinetics, Chromatography, High Pressure Liquid

Abstract

Background: Intracranial 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.
Methods: This was a randomized clinical trial in which 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.
Results: 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.
Conclusion: 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.

References

Castellanos M, Freijo MM, Fernández JCL, et al. Clinical practice guidelines in intracerebral haemorrhage. Neurologia 2013;28(4):236-49.
2. Dastur CK, Yu W. Current management of spontaneous intracerebral haemorrhage. Stroke and Vascular Neurology 2017;2(1):21-9.
3. Hemphill JC, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke 2015;46(7):2032-60.
4. Hwang BY, Appelboom G, Ayer A, 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, et al. An update on the use of melatonin as a stroke therapeutic. Minerva Med 2015;106(3):169-75.
6. Andrabi SS, Parvez S, Tabassum H. Melatonin and ischemic stroke: Mechanistic roles and action. Adv Pharmacol Sci 2015;2015:384750.
7. Wu HJ, Wu C, Niu HJ, et al. Neuroprotective Mechanisms of Melatonin in Hemorrhagic Stroke. Cell Mol Neurobiol 2017;37(7):1173-85.
8. Mistraletti G, Sabbatini G, Taverna M, 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, 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. 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, 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 1999;317(5):278-81.
13. Frisk U, Olsson J, Nylén P, Hahn RG.. Low melatonin excretion during mechanical ventilation in the intensive care unit. Clin Sci (Lond) 2004;107(1):47-53.
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, et al. Measurement of serum melatonin in intensive care unit patients: Changes in traumatic brain injury, trauma and medical conditions. Front Neurol 2014;5:237.
16. Agha A, Rogers B, Mylotte D, 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 2002;33(4):248-52.
18. Bonnefont-Rousselot D, Collin F. Melatonin: Action as antioxidant and potential applications in human disease and aging. Toxicology 2010;278(1):55-67.
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 2005;31(3):327-37.
21. Lovat R, Preiser J-C. Antioxidant therapy in intensive care. Curr Opin Crit Care 2003;9(4):266-70.
22. Shilo L, Dagan Y, Smorjik Y, et al. Effect of Melatonin on Sleep Quality of Copd Intensive Care Patients: a Pilot Study. Chronobiol Int 2000;17(1):71-6.
23. Ibrahim MG, Bellomo R, Hart GK, 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, et al. Melatonin pharmacological blood levels increase total antioxidant capacity in critically ill patients. Int J Mol Sci 2017;18(4):759.
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 2008;12(2):R52.
29. Hemphill JC 3rd1, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH Score; a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32(4):891-7.
30. Center for Drug Evaluation and Research (CDER). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. Washington: U.S. Department of Health and Human Services, Food and Drug Administration; 2005 [updated date 2018; cited 2019 nov 23]. Available from: http://www.fda.gov/downloads/Drugs/Guidance/UCM078932.pdf
31. Department of Health, Therapeutic Goods Administration. Australian Public Assessment Report for Tocilizumab- Proprietary Product Name : Actemra Sponsor : Roche Products Pty Ltd. Woden Valley: Therapeutic Goods Administration department of health; 2016 [cited 2019 Oct 25]. Available from: https://www.tga.gov.au/sites/default/files/auspar-vismodegib-130913.pdf
32. Ueda Y, Masuda T, Ishida A, 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 AB, Jacob S. A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 2016;7(2):27-31.
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 Analyt Technol Biomed Life Sci 2009;877(22):2173-7.
35. Karasek M, Winczyk K. Melatonin in humans. J Physiol Pharmacol 2006;57(5Suppl):19-39.
36. Powers WJ. Intracerebral hemorrhage and head trauma: Common effects and common mechanisms of injury. Stroke 2010;41(10 Suppl):S107-10.
37. Kilic U, Yilmaz B, Ugur M, 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, et al. Measurement of melatonin in body fluids: Standards, protocols and procedures. Childs 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. 2000;40(7):781-4.
42. Zhdanova I V., Wurtman RJ, Balcioglu A, Kartashov AI, Lynch HJ. Endogenous melatonin levels and the fate of exogenous melatonin: Age effects. J Gerontol Ser A Biol Sci Med Sci 1998;53(4):B293-8.
43. Mallo C, Zaidan R, Galy 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, et al. Time course of saliva and serum melatonin levels after ingestion of melatonin. Psychiatry Clin Neurosci 1998;52(2):266-7.
Published
2020-03-24
How to Cite
1.
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.
Section
Original Article(s)