EXOGENOUS MELATONIN AS A POTENTIAL COAJUVANT AGENT IN THE CURRENT SARS-CoV-2 PANDEMIC

Author: Dr. Antonio E. Jerez Calero

INTRODUCTION/GENERALITIES

 

Melatonin is a physiologically secreted hormone in the pineal gland. It is responsible, among many other functions, for the regulation of the circadian cycles and therefore for the wakefulness and sleep cycles. Due to its lipophilic properties, melatonin easily passes through most cell membranes, including the placenta and the blood-brain barrier. Its actions are not only mediated by specific receptors, but also have an intrinsic function as an antioxidant and with an antiapoptotic effect. It has multiple endocrine, autocrine and paracrine actions that affect an enormous number of human organs and systems (Reiter, 1995; Acuña-Castroviejo, 1995; Acuña-Castroviejo, 2001)

 

BIOAVAILABILITY, METABOLISM AND ROUTES OF ADMINISTRATION

 

Oral bioavailability is good in patients without serious pathologies; the currently recommended doses (1-5 mg) for the classic “jet lag” produce plasma concentrations in 1 hour that are 10 to 100 times higher than the maximum night peak, to drop to normal values in 4-8 hours (orally they have an average life of 3 hours 45 minutes). Low doses (0.1-0.3 mg) administered during the day produce levels that are within the normal night range. After administration, in addition to blood, saliva and urine, melatonin is detected in CSF (with concentrations much higher than blood, in the anterior chamber of the eye (blood-like levels) as well as in semen, amniotic fluid, breast milk and preovulatory follicles. It has a biphasic elimination pattern: about 90% is eliminated through the liver and a small proportion is not metabolized, through the urine (Acuña-Castroviejo, 1995).

 

For exogenous administration the oral route could be used, but the absorption and bioavailability in seriously ill patients would be erratic and difficult to quantify accurately. The intravenous formulation is the only way that would guarantee exact and stable levels, especially in critically ill patients.

 

TOXICITY

 

Regarding its toxicity at high doses, the lethal dose 50 could not be found in numerous experimental animal studies. Therefore, it is not a non-toxic substance in any case. In children, mild symptoms such as nausea, apathy, weight gain, nocturnal enuresis, and headache have been described in some cases. In a follow-up trial, it has been shown that melatonin treatment in children can be used for long periods of time, without any alteration in the child’s development regarding sleep quality, pubertal development and scores on mental health scales, compared to the general population. In animals, very diverse doses of melatonin and over a wide range of doses have been used to treat brain injury. An intraperitoneal melatonin dose of 0.005 mg / kg is neuroprotective in newborn mice and doses of up to 200 mg / kg have been administered to pregnant rats throughout most of pregnancy with no adverse effects to the mother or newborn. The optimal dose will undoubtedly be different depending on the effect required. Melatonin has been used safely in children with sleep disturbances related to neurological disease and in septic newborns without serious adverse effects (Reiter, 2014).

 

Maternal administration of melatonin (1 mg bolus and then 1 mg / h for 2 hours) also prevented the subsequent increase in free radical production in the ovine fetus exposed to intrauterine asphyxia. A low dose (0.1 mg / kg / day) administered to the mother for 7 days in late pregnancy reduces signs of brain inflammation and apoptosis after perinatal asphyxia in mice. The evidence emanating from both clinical and experimental studies supports the safety of melatonin in the prenatal period, without teratogenic or toxic effects.

 

A study recently published in the prestigious scientific journal Pediatric Critical Care Medicine is the first to report, in humans, a randomized, multicenter, controlled clinical trial of intravenous melatonin administration to severely asphyctic infants. An intermediate and final safety analysis was performed in which biochemical parameters in blood and urine were measured, as well as neuroimaging results and neurophysiological studies. Among the remarkable findings, the feasibility and safety of its administration in these critically ill infants admitted to the ICU are corroborated. In addition, better long-term neurodevelopmental results (18 months of age) were obtained in the group of neonates treated with melatonin compared to placebo (neuroprotective effect). (Jerez-Calero, 2020)

 

Therefore, no serious reactions have been reported in the few clinical trials with neonates treated with intravenous melatonin.

 

 

MELATONIN AND IMMUNITY

 

There is a large body of evidence for the ability of melatonin administration in both in vivo and in vitro models. Different studies have shown that treatment with melatonin favors the increase in weight of immune organs, both under normal conditions and in immunosuppressed patients.

 

Generically, some functions related to immunity, demonstrated in the scientific literature include the following:

 

  1. In experimental animals:

 

  • Increases the total number of leukocytes and lymphocytes

 

  • Produces splenic hypertrophy and extramedullary hematopoietis

 

  • Increases the count of macrophages, NK cells and monocytes

 

  • Increases the humoral response (Ig G1 and IgM) (Carrillo-Vico, 2013)

 

  • Restores chemotaxis when altered, mitogenic response, IL-2 release and NK cell activity.

 

  • Increases the weight of the thymus and the functions of T, B and NK cells. (Carrillo- Vico, 2005; Luo, 2020)

 

  • Modulates inflammatory processes regulating the recruitment of leukocytes (Perfilyeva, 2019). This immunomodulation has been useful to decrease lung damage in rats that were induced exogenous chemical damage, if they were treated with exogenous melatonin prior to administration (Al-Rasheed, 2017).

 

  1. In humans:

 

  • Increases the chemotactic response of neutrophils to physiological substances and the expression of intracellular cytokines (Pena, 2007)

 

  1. IN vitro:

 

  • Improves bacterial inhibition of M. tuberculosis in vitro three to four times compared to conventional therapy. [Wiid, 1999]

 

  • Decreases the in vitro growth of Leishmania amazonensis (Fernandes, 2019)

 

  • It is capable of controlling the growth of tumors induced by viruses, such as the human papilloma, when melatonin is added to conventional immunosuppressive therapy (Moreno, 2018).

 

If we analyze the scientific works based on the pathogen studied:

 

  1. In bacterial infections:

 

  • Improvement of bacterial sepsis in numerous studies worldwide, using experimental models, after exogenous addition of melatonin. The mechanisms of action of melatonin reflect the pleiotropic capacity of the molecule. It is capable of blocking the overproduction of inflammatory cytokines, especially interferon-α, and increases levels of interleukin 10.

 

  • Effects, not only in direct immunomodulation, but also combats bacterial sepsis thanks to its antioxidant capacity demonstrated in models of sepsis induced in experimental animals (Erbaş, 2012; Hu, 2017)

 

  • For two decades, there have been studies detailing the improvement, in septic processes, of the chelating capacity of free radicals from oxygen or nitrogen in rodents (Crespo, 1999; Wu, 2001)

 

  • By administering exogenous melatonin to a group of rats, it has been demonstrated biochemically and clinically effective when sepsis is induced. In the rodent groups treated with melatonin, they showed less apoptosis, less inflammatory activity and less kidney, liver and heart damage, with significant differences. (Dai, 2019; Chen, 2019; Zhang, 2019).

 

  • In humans, the administration of exogenous melatonin has shown an improvement in the clinical results in septic newborns, by reducing lipid peroxidation and improving the number of leukocytes and neutrophils in PCR levels (Gitto, 2001). In addition, melatonin reduces the production of proinflammatory cytokines (IL-6, IL-8, TNF-α) and nitrate levels in preterm infants with respiratory distress syndrome. These preterms with chronic pulmonary pathology (called bronchopulmonary dysplasia, which occurs with hypercapnia and / or hypoxia) have also been improved thanks to the administration of melatonin (Gitto, 2005). It is considered a molecule with proven promising effects, even in the treatment of neonatal sepsis (El-Gendy, 2018; D´Angelo, 2017).

 

  1. In parasitosis

 

It is capable of improving Chagas disease in infected rats (Brazao, 2020).

The same has been shown in amebiasis, giardiasis, leishmaniasis and malaria (Daryani, 2018)

 

  1. In viral infections:

 

  • Administered to mice infected with the Venezuelan encephalomyelitis virus, it was shown to reduce mortality from 100% to 16% (Bonilla, 1997).

 

  • Increases serum levels of TNF-α, IL-1β and IFN-γ. (Valero, 2002)

 

  • The administration of melatonin reduces the concentrations of lipid peroxidation products in infected mice (Valero, 2007).

 

  • It could play a determining role by directly inhibiting the replication and proliferation of pathogens, making it a new method of fighting against infectious diseases (Ma, 2019)

 

  • In Ebola virus infections, normalization of Natural killer (NK) cells seems crucial for survival. Well, melatonin increases the cytotoxicity of NK cells significantly, so it suggests antiviral efficacy in these cases. (Anderson, 2015)

 

Some authors affirm that exogenous administration of melatonin could have an important role in the prevention of septic shock in ICUs, this being the most serious clinical form of infection in humans (Marra, 2019). There is accumulated scientific evidence of the role of melatonin in the regulation of damaged autophagic processes, such as aging, cancer, obesity, neurodegenerative diseases and viral infections (Boga, 2019).

 

In general, all available evidence supports that exogenous melatonin could act as an immunostimulatory and immunomodulatory substance in both healthy and immunosuppressed individuals. It would be able to provide an earlier and more effective start of the immune response against invading microorganisms, such as bacteria, viruses or parasites. (Carrillo-Vico 2013).

 

The demonstrated potential effects and the excellent safety profile suggest that exogenous melatonin is an excellent complement to other analgesic, sedative, anti-inflammatory and anti-infective drugs for use in critically ill patients (Marra, 2019)

 

 

CONCLUSION

 

For all the above, I hypothesize that intravenous melatonin could become an adjunctive therapy, in association with all currently accepted measures and treatments, to fight against COVID-19.

 

 

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JEREZ CALERO ANTONIO EMILIO – 44285440K Digitally signed by JEREZ CALERO ANTONIO EMILIO – 44285440K

Date: 2020.03.18 15:18:21

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