Please cite this paper as:
Brusco, L., Brusco, L., Cruz, P., Cangas, A., Rojas, C., Vigo, D. and Cardinali, D. 2021. Efficacy of melatonin in non intensive care unit patients with COVID-19 pneumonia and sleep dysregulation. Melatonin Research. 4, 1 (Jan. 2021), 173-188. DOI:https://doi.org/https://doi.org/10.32794/mr11250089.
Review
Efficacy of melatonin in non-intensive care unit patients with COVID-19 pneumonia and sleep dysregulation
Luis I. Brusco1, Pablo Cruz2, Alicia V. Cangas2, Carmen González Rojas2, Daniel E. Vigo3,4 and Daniel P. Cardinali3*
1Faculty of Medicine, University of Buenos Aires, Argentina
2Centro Gallego of Buenos Aires, Argentina
3Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina
4Institute for Biomedical Research, Pontificia Universidad Católica Argentina and Argentine National Research Council (CONICET), Buenos Aires, Argentina
*Correspondence: daniel_cardinali@uca.edu.ar, Tel: +5491144743547
Running title Melatonin and COVID-19 pneumonia
Received: November 6, 2020; Accepted: December 23, 2020
ABSTRACT
The association of sleep disruption with a higher vulnerability to COVID-19 infection is a subject of major clinical importance. In patients with pneumonia associated with COVID-19 admitted to non-intensive care unit (NICU) several factors, like the disrupting influence of respiratory distress, medication, greater stress due to social isolation, and lack of appropriate exposure to environmental light can be instrumental to disrupt sleep/wake cycle. The therapeutic potential of melatonin to counteract the consequences of COVID-19 infection has been advocated. Because of its wide-ranging effects as an antioxidant, anti-inflammatory, and immunomodulatory compound, melatonin could be unique in impairing the consequences of SARS-CoV-2 infection. Melatonin is also an effective chronobiotic agent to reverse the circadian disruption of social isolation and to control delirium in severely affected patients. Properly administered, melatonin may restore the optimal circadian pattern of the sleep-wake cycle and improve clinical condition in pneumonia associated with COVID-19 patients. The present review article discusses the importance of maintaining normal sleep and circadian rhythmicity in NICU patients and provides preliminary data suggesting the efficacy of melatonin (9 mg/day) to reduce length of stay of pneumonia patients associated with COVID-19 in NICU.
Key words: Chronotherapy, COVID-19 pandemic, melatonin, pneumonia, respiratory distress, sleep.
______________________________________________________________________________
1 INTRODUCTION
In pneumonia associated with COVID-19 patients admitted to non-intensive care unit (NICU) several factors, like the disrupting influence of respiratory distress, medication, greater stress due to social isolation and erratic exposure to environmental light are instrumental to disrupt the sleep/wake cycle. Sleep deprivation and abnormal melatonin excretion are associated with the occurrence of delirium, a frequently encountered dysfunction in critically ill patients (1). Delirium is a consciousness disorder with cognitive change (hyperactive, hypoactive, or mixed form) and is a well-known risk factor for prolonged duration of intensive care unit (ICU) stay, higher mortality, greater risk of cognitive sequelae, and more hospital costs (1).
The potentiality of melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, to serve as a preventive and therapeutic agent in COVID-19 pandemic has been advocated (2, 3). Melatonin (a) may prevent SARS-CoV-2 infection; (b) is suitable as an effective anti-inflammatory/immunoregulatory/antioxidant agent; (c) counteracts chronodisruption; (d) combats several comorbidities such as diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases, which aggravate COVID-19 disease; (e) exerts a neuroprotective effect in acutely and chronically affected SARS-CoV-2 patients; and (f) can be an adjuvant to potentiate anti-SARS-CoV-2 vaccines (see for ref. (4). This multifactorial therapeutic potential is unique to melatonin and is not shared by any other therapeutic drug candidate for the COVID 19 pandemic.
As a chronobiotic agent, melatonin may restore the optimal circadian pattern of the sleep / wake cycle and improved clinical condition in individuals with COVID-19 pneumonia admitted to NICU. We hereby discuss the importance of sleep and circadian rhythm regulation in pneumonia associated with COVID-19 patients in ICU and provide preliminary data suggesting the efficacy of melatonin (9 mg/day) to reduce NICU length of stay in those patients.
2. SLEEP / WAKE CYCLE IN NON-INTENSIVE AND INTENSIVE CARE UNIT
Human sleep is organized by the interaction of homeostatic and circadian processes that are carried out independently, but in a complementary way. The homeostatic component (process S, for “sleep”) leads to sleep approximately one third of each 24-hour cycle, and the circadian component (process C) links the desire to sleep with the daily fluctuations of hormones programmed by the body clock. This two-process model of sleep, first proposed by Borbély in 1982, explains how homeostatic and circadian factors regulate the quantity and timing of sleep (5) According to this model, the requirement for sleep increases during wakefulness because of homeostatic process S in the brain (“sleep debt”) while circadian process C reflects circadian modification of vigilance. Borbély’s theory states that the likelihood of wakefulness and sleep are traded off against one another in a circadian mode. Homeostatic process S is defined as a homeostatic sleep-promoting process, which continuously escalates during wakefulness. Process S is related to decreased intellectual performance and vigilance, and an increase in sleepiness/fatigue while awake. During sleep, particularly slow wave sleep, process S continuously decreases (i.e., sleep pressure disintegrates). In contrast, the circadian scheduled process C (also known as the circadian pacemaker) is best seen as a nearly 24 h endogenous oscillatory variation for sleep propensity (5).
According to the classical view, the preoptic area (POA) and the posterior hypothalamus are thought to be the sleep and wake centers, respectively (6). More recently, new brain areas and neurons involved in the regulation of the sleep/wake cycle have been uncovered. For example, GABAergic neurons in the medullary parafacial zone located in the brain stem and the ventral tegmental area (7) and adenosine expressing neurons in the nucleus accumbens are involved in the regulation of rapid eye movement (REM) sleep, whereas the MT2 receptors selectively increase non-REM sleep (8). While the POA contains not only sleep-promoting neurons but also wake-promoting neurons (9), noradrenergic neurons in the locus coeruleus, serotonergic neurons in the dorsal raphe, and histaminergic neurons in the tuberomammillary nucleus are only implicated in regulation of wakefulness (10). Orexin/hypocretin neurons in the lateral hypothalamus play a crucial role to maintain wakefulness by orchestrating the activity of these monoaminergic neurons (11).
Sleep deprivation and poor sleep quality are problems in patients admitted in NICU, as reported in a study of 100 patients with low levels of sleep quality from Canadian general or family practice wards (12). In this type of patients, most studies reported difficulties during night sleep, even without previous sleeping problems at home (13–15).
These disorders worsen in ICU patients. The therapeutic procedures and medication and inappropriate lighting conditions contribute to disruption of the normal sleep / wake cycle in ICU (16–18). Increased pain sensitivity, reduced respiratory capacity, impaired immunity, and changes in neuroendocrine and metabolic functions have been reported in ICU patients (see for ref. (19). Additionally, consequences of sleep deprivation like memory impairment and mood deficits and delirium occur (20). Therefore, normalization of sleep in pneumonia associated with COVID-19 patients is instrumental to improve secondary outcomes including ICU length of stay and post-ICU recovery and functioning (18).
A mixture of medications including analgesic, sedative and hypnotic agents are often used in the ICU to reduce patients’ pain or awareness of their environment, reduce responses to external stimulation, and eventually facilitate endotracheal tube tolerance and mechanical ventilator synchrony. Approximately 25% of ICU patients were prescribed eight or more medications concurrently and, of those patients, the average number prescribed was more than 13 (21). However, many negative side-effects emerge with the use of these medications, including impaired cognitive function, risk of dependency, depressed ventilation, and disrupted sleep patterns.
By measuring blood and urine melatonin levels the abolition of the circadian rhythm of physiologic melatonin release was documented in sedated ICU patients (22). This may be due to the exposure to artificial light and limited natural light exposure, greater severity of illness compared with the general wards, and universal application of sedative and narcotic drugs, which may further contribute to a compromised quality of sleep. About 15% of hospitalized COVID-19 patients have impaired consciousness including somnolence, confusion and delirium (23). Indeed, about 50% of hospitalized elderly patients and 80% of critically ill patients under mechanical ventilation shows sleep disturbances and delirium (17, 24). All these indicate a profound alteration in the duration and organization of sleep.
Circadian disruption by sleep loss, like that observed in COVID-19 patients admitted to ICU, affects every major system in the human body. Several epidemiologic studies have reported associations between sleep/wake cycle disruption and cardiometabolic disease (25, 26). Shortened sleep and poor sleep quality have also been identified as risk factors for cognitive decline, neurodegenerative disease, mood changes and depression, as well as other neuropsychiatric conditions (27, 28). There is also mounting evidence linking sleep disruption to immune function and cancer (29–31).
3. MELATONIN AND SLEEP
The circadian rhythm in synthesis and secretion of pineal melatonin is closely associated with the sleep rhythm (32). The onset of nighttime melatonin secretion is initiated approximately 2 h in advance of an individual’s habitual bedtime and has been shown to correlate with the onset evening sleepiness. Several studies implicate endogenous melatonin in the physiological regulation of the circadian mechanisms ruling sleep propensity (33). Melatonin reduces the need for sedation in ICU patients (34–39). Thus, in the context of COVID-19 pandemic the therapeutical utility of melatonin emerges.
Melatonin is a prototype chronobiotic that plays a major function in the coordination of circadian rhythmicity (40). Drugs that directly affect the circadian phase, and thus the output of the biological clock, are called chronobiotics. This term was introduced in the early 1970s and has been used to broadly define a drug that affects the physiological regulation of the structure of biological time and, specifically, is capable of therapeutically recovered desynchronized circadian rhythms in the short or long term, or prophylactically avoiding its interruption after an environmental attack (41). The magnitude and direction of phase changes depend on the circadian phase in which these compounds are administered, which in turn produces pronounced phase changes in behavioral rhythms. For example, melatonin given in the morning delays the phase of circadian rhythms while when given in the evening it advances the phase of circadian rhythms. For most part of the day, melatonin administration is unable to modify the phase of the clock (phase response curve).
During the day-to-night transition, melatonin exposure advances neural activity rhythms in the central circadian pacemaker located at the hypothalamic suprachiasmatic nuclei (SCN) via the activation of protein kinase C. Melatonin induces an increase in the expression of two SCN clock genes, Period 1 (Per1) and Period 2 (Per2). This effect occurs at circadian time (CT) 10, when melatonin advances SCN phase, but not at CT 6, when it does not. Using anti-sense oligodeoxynucleotides to Per1 and Per2, as well as to E-box enhancer sequences in the promoters of these genes, it was shown that their specific induction is necessary for the phase altering effects of melatonin on SCN neural activity rhythms (42).
Melatonin secretion is an “arm” of the biologic clock in the sense that it responds to signals from the SCN and that the timing of the melatonin rhythm indicates the status of the clock, both in terms of phase (i.e., internal clock time relative to external clock time) and amplitude (43). From another point of view, melatonin is also a chemical code of night: the longer the night, the longer the duration of its secretion. In most vertebrate species, this pattern of secretion serves as a time cue for seasonal rhythms (44).
Pineal melatonin production is controlled by a complex neural system originating in the SCN and terminating in the high levels of the thoracic spinal cord – the superior cervical ganglion sympathetic system. The postganglionic sympathetic nerve terminals of the superior cervical ganglion release norepinephrine into the pineal gland that triggers melatonin synthesis by its interaction with β- (mainly) and α-adrenoceptors on the membrane of pineal cells. Melatonin, due to its high diffusibility, is not stored inside the pineal and is released as soon as it is produced (45). The structures which regulate circadian rhythms have been described as the SCN-melatonin loop (45). This loop includes melanopsin-containing retinal ganglion cells, the retino-hypothalamic tract, SCN, paraventricular nucleus, intermediolateral cell column, the sympathetic cervical ganglia, the pineal gland, and the melatonin rhythm which feedback impacts the SCN.
As a result, the melatonin production, and consequently its cerebrospinal fluid and blood levels, are circadian in nature and tightly synchronized with the environmental light/dark cycle. Indeed, the circadian pineal production of melatonin is restricted to the dark phase of the light/dark cycle in all mammalian species. It is noteworthy that melatonin is always produced during the night independent of the daily pattern of activity/rest of the species, indicating its strong relationship with the external photoperiod. Additionally, melatonin is produced during the night provided there is no light in. Given the regularity of the daily melatonin production that is associated with high and low or absent blood concentrations during the night and day, respectively, melatonin is able to synchronize the circadian rhythms of several organs and their functions (43)
Daily timed administration of melatonin to rats shifts the phase of the circadian clock, and this phase shifting may explain the effect of melatonin on sleep in humans. Indirect support for such a physiological role derives from clinical studies on blind subjects (who show free running of their circadian rhythms) treated with melatonin (46). More direct support for this hypothesis was provided by the demonstration that the phase response curve for injected melatonin was opposite (i.e., about 180 degrees out of phase) to that of light (47).
Melatonin is a pleiotropic signal that has to be analyzed at different levels, from the sites of synthesis and local dynamics, distribution of receptors and other binding sites in target organs, cell-specific differences in signaling as related to the presence of G protein variants, and intracellular effects – with a particular focus on mitochondrial actions – to numerous secondary changes induced by influencing other hormones, neurotransmitters, neurotrophins and further signal molecules (48). In functional terms, melatonin exerts a host of effects that can be under the control of the SCN and has also direct effects in numerous peripheral organs. In particular, melatonin is involved in sleep initiation, vasomotor control, adrenal function, antiexcitatory actions, immunomodulation including anti-inflammatory properties, antioxidant actions, and energy metabolism, influencing mitochondrial electron flux, the mitochondrial permeability transition pore, and mitochondrial biogenesis (48, 49).
The chronobiotic action of melatonin is mediated via the melatonin receptors, which have been identified both in the central nervous system and in the periphery (50). Melatonin MT1 and MT2 receptors, all belonging to the superfamily of membrane receptors associated with G proteins (G-protein coupled receptors, GPCR), have been cloned. More recently, another member, GPR50, was included in the melatonin receptor subfamily. GPR50 shows high sequence homology to MT1 and MT2 but does not bind to melatonin or any other known ligand. Ligand-independent functions for GPR50 such as the allosteric regulation of other proteins/receptors through their interaction with GPR50 in common protein complexes have been proposed. In the case of the molecular complex of GPR50 with the melatonin MT1 receptor, GPR50 negatively regulates the function of MT1 (51).
Circulating melatonin is loosely bound to albumin (52) and in the liver, it is first hydroxylated and then conjugated with sulfate and glucuronide (53). In human urine, 6-sulfatoxymelatonin has been identified as the main metabolite. In the brain and most peripheral cells melatonin is metabolized into kynurenine derivatives. In mammals, circulating melatonin is derived almost exclusively from the pineal gland. In addition, melatonin is synthesized locally in most cells, tissues and organs, including lymphocytes, bone marrow, thymus, gastrointestinal tract, skin and eyes, where it can play an autocrine or paracrine role (54). Indeed, there is now strong evidence that melatonin is produced in every animal cell that has mitochondria (55). In both animals and humans, melatonin participates in diverse physiological functions that indicate not only the duration of the night, but also improve the elimination of free radicals and the immune response, showing relevant cytoprotective properties.
Concerning the sleep/cycle, melatonin is a powerful chronobiotic with very slight hypnotic capacity. Daily doses of 2-5 mg melatonin, timed to advance the phase of the internal clock by interaction with MT1 receptors in the SCN, maintains synchronization of the circadian rhythms to a 24-h cycle in sighted persons who are living in conditions likely to induce a free-running rhythm (47). Melatonin synchronizes the rhythm in persons after a short period of free running. In blind subjects with free-running rhythms, it has been possible to stabilize, or entrain, the sleep/wake cycle to a 24-h period by giving melatonin, with resulting improvements in sleep and mood (46). The phase shifting effect of melatonin is also sufficient to explain its effectiveness as a treatment for circadian-related sleep disorders, such as jet lag or delayed phase sleep syndrome (56, 57). Recent advances using selective MT1/MT2 receptor ligands and MT1/MT2 receptor knockout mice have suggested that the activation of the MT1 receptors is mainly implicated in the regulation of REM sleep, whereas the MT2 receptors selectively increase non-REM sleep (58).
Several meta-analyses support the view that the chronobiotic/hypnotic properties of melatonin are useful in patients with primary sleep disorders to decrease sleep onset latency and to increase total sleep time, with little if any effect on sleep efficiency (59–61). Several expert consensus reports also support such a role of melatonin in adult insomnia (62–65).
In normal aged subjects and in demented patients with disturbed synchronization of the sleep/wake cycle (66, 67) melatonin administration is helpful to reduce the variation of onset time of sleep. In demented patients, melatonin improved the circadian rhythm, cognition and mood, and diminishes nocturnal restlessness (68). In the long term, melatonin administration halted evolution of minimal cognitive decline to Alzheimer´s disease. This effect may be relevant in the control of residual effects of COVID 19 disease. Indeed, in a recent study including 84,285 Great British Intelligence Test with biologically confirmed COVID-19 infection, people who had recovered, including those no longer reporting symptoms, exhibited significant cognitive deficits (69). The scale of the observed deficits was equivalent to the average 10-year decline in global performance between the ages of 20 to 70 within the same dataset. “Brain fog”, i.e., confusion, forgetfulness, inability to focus, fatigue, and low mental energy (70, 71) is thus an emerging major sequel of COVID-19 infection. In this context the neuroprotective properties of melatonin deserve consideration (72).
4. MELATONIN USE IN COVID-19 PANDEMIC
In severely infected patients with COVID-19, an excessive inflammation, a depressed immune system, and activated cytokine storm contribute substantially to pathogenesis. In light of the public health problem triggered by the spread of COVID-19 and in the face of essentially null options for prevention or treatment presently available, a number of recent reports have put forth the use of melatonin to treat COVID-19 disease (73–81).
In diseases showing a high level of inflammation, the application of melatonin showed promising results with strong attenuation of circulating cytokine levels. This was documented in patients with diabetes mellitus and periodontitis (82) and severe multiple sclerosis (83). In the acute phase of inflammation, during surgical stress (84), cerebral reperfusion (85) or reperfusion of the coronary artery (86), treatment with melatonin reduced the level of proinflammatory cytokines.
According to the COVID-19 clinical reports, patients with severe infection have an increased risk of sepsis and cardiac arrest (87, 88). The available information indicates that the application of melatonin can improve septic shock through inhibition of the NLRP3 inflammasome pathway (89). Interestingly, the upregulation of matrix metalloprotease 9 MMP9 (activated during NLRP3 inflammasome) was found to be correlated with COVID-19 related cytokine storm (79), and a recent meta-analysis indicates that melatonin may interact with MMP9 in the extracellular matrix of the respiratory tract from the SARS-CoV-2 patients to reduce inflammation during COVID-19 infection (80).
Melatonin has a preventive effect against sepsis-induced kidney damage, septic cardiomyopathy, and liver damage (90–92). Melatonin has also been reported as beneficial in patients with myocardial infarction, cardiomyopathy, hypertensive heart disease, and pulmonary hypertension. In the ICU, deep sedation is associated with increased long-term mortality, and the application of melatonin reduces the use of sedation and the frequency of pain, agitation and anxiety and improves the quality of sleep (93). Therefore, the rationale for the use of appropriate doses of melatonin in COVID-19 focuses not only on attenuation of infection-induced respiratory disorders, but also on general improvement and prevention of possible complications, like the cardiac and neurologic ones.
Another recent report was a retrospective analysis based on the clinical experience at the Columbia University Irving Medical Center related to drugs used to treat respiratory distress in COVID-19-infected patients who required endotracheal intubation (95). After a comprehensive evaluation of 791 patients diagnosed with COVID-19 who required intubation, the application of melatonin is the only drug that was statistically associated with higher positive clinical outcome including survival of patients intubated and in those requiring mechanical ventilation. Presently 8 clinical trials looking for melatonin therapeutic effects in COVID pandemic are in different phases of development (https://clinicaltrials.gov/).
5. PRELIMINARY OBSERVATION ON MELATONIN EFFICACY IN PNEUMONIA ASSOCIATED WITH COVID-19 PATIENTS PNEUMONIA ADMITTED TO NICU
Sleep deficiency is one of the most common complains in patients with respiratory diseases, and insomnia results in a significant deterioration in respiratory performance, even in a healthy person (96). Indeed, sleep disruption has been reported as extremely common in the pulmonary ICU (97).
Table 1. NICU, laboratory-confirmed, pneumonia associated with COVID-19 patients treated (Buenos Aires) or non-treated (New York) with melatonin.
Centro Gallego of Buenos Aires n=37 n (%) or mean (SD) |
New York metropolitan region (98) n=60 n (%) or mean (SD) |
p |
|||
Female |
17 (45.9%) |
8 (13.3%) |
< 0.001 a |
||
Age (years) |
60.2 (19.4) |
58.7 (13.4) |
ns c |
||
Length of stay (days) |
4.9 (2.6) |
10.7 (8.4) b |
< 0.001 c |
||
Death |
1 (2.7%) |
8(14.6%) |
ns a |
||
a. chi square test; b. Length of stay Mean and SD were estimated from median and interquartile range values reported in (98). Calculations were conducted as described elsewhere (99). c. Student’ t-test; ns: non-significant.
In a recent therapeutic algorithm for the use of melatonin in patients with COVID-19 a dose of 3 to 10 mg/day dose of melatonin was proposed for elderly patients with co-morbidities like sleep disruption (100). We employed a 9-mg melatonin dose to improve clinical conditions and hastened recovery in a group of 37 hospitalized patients with COVID-19 pneumonia (Table 1). This was a retrospective cohort study of a limited clinical database of confirmed pneumonia associated with COVID-19 patients hospitalized at Centro Gallego of Buenos Aires. All patients were diagnosed as per the World Health Organization’s interim guidance document. Collected information on consecutive patients admitted to the general ward from August 31, 2020, to September 11, 2020, as per our inclusion and exclusion criteria, was obtained. The ethics committee of Centro Gallego of Buenos Aires approved this study and permitted a waiver of informed consent from the study participants.
Patients were eligible for the study if they met the following inclusion criteria 1) Age > 18 years old, 2) Confirmed cases of SARS-CoV-2 by PCR method, 3) Admitted in general ward, 4) Bilateral infiltrate on chest imaging validated by radiology staff. Nasopharyngeal swab samples were obtained from all patients at admission and tested using real-time reverse transcriptase-polymerase chain reaction assays to identify SARS-CoV-2 infected patients. Limited available information included sex, age, length of stay and outcome (discharge or ICU transfer). All patients were on corticosteroid treatment and received 9 mg of melatonin p.o. at 2200 h daily. The primary outcomes were the composite outcome of intensive care unit (ICU) transfer, intubation, or death and length of stay. No relevant side effect of melatonin was recorded in the sample of patients examined.
Results are summarized in Table 1. As a comparison, data from a NICU, laboratory-confirmed, COVID-19 pneumonia study performed in the New York metropolitan region were employed, considering only the subgroup of patients under corticosteroid treatment (98). Although we cannot discard that patients from our study were less severely affected than those from the New York series, melatonin administration reduced by half the length of stay of pneumonia associated with COVID-19 patients. It must be stressed that this is a retrospective cohort study of a limited clinical database from which, unfortunately, no more information was available, like for example, that derived from non COVID-19 patients hospitalized in the same NICU. Clearly, the samples in Table 1 might not be comparable, and the possible effect of melatonin in reducing length of stay needs further examination.
6. CONCLUSIONS
The current COVID-19 pandemic is the most devastating event in recent history. As above discussed, in the ICU, deep sedation is associated with increased long-term mortality, and the application of melatonin reduces the use of sedation and the frequency of pain, agitation and anxiety and improves the quality of sleep. Properly administered, the chronobiotic/cytoprotective agent melatonin may restore the optimal circadian pattern of the sleep-wake cycle and improve clinical condition in individuals with COVID-19 pneumonia.
A recent study endorses the efficacy and tolerability of a high dose of melatonin as an adjuvant therapy in ICU patients, in addition to standard and/or empirical therapy for COVID-19 pneumonia (94) and preliminary data of Table 1 suggesting the efficacy of a relatively low dose of melatonin to reduce NICU length of stay in pneumonia associated with COVID-19 patients support such a view.
Melatonin has been used as a sleep aid for decades without any serious adverse effects being reported (101, 102). Moreover, it has often been used in critically ill patients to improve sleep and wellbeing, both of which would also be beneficial to SARS-CoV-2 infected patients. It is a molecule with an uncommonly high safety profile and can be administered via numerous routes including orally. It is inexpensive, stable without refrigeration and would be particularly useful in underdeveloped countries where access to high quality health care may be lacking.
ACKNOWLEDGEMENT
L.I.B. and D.E.V. are Independent Investigators from CONICET. D.P.C. is an Emeritus Superior Investigator from CONICET and Emeritus Professor, University of Buenos Aires.
AUTHORSHIP
Conceptualization: D.P.C., L.I.B., D.E.V. Writing, Original draft: D.P.C. Writing, Review & Editing: D.P.C., L.I.B., D.E.V., P.C., A.V.C., C.G.R. Data curation: L.I.B, P.C., A.V.C., C.G.R.
CONFLICT OF INTEREST
All authors declare that they have no proprietary, financial, professional, nor any other personal interest of any nature or kind in any product or services and/or company that could be construed or considered to be a potential conflict of interest that might have influenced the views expressed in this manuscript.
REFERENCES
Maldonado JR, Kapinos G (2008) Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit. Care Clin. 24: 789–856. https://doi.org/10.1016/j.ccc.2008.06.004.
Zhang R, Wang X, Ni L, Di X, Ma B, Niu S, et al. (2020) COVID-19: Melatonin as a potential adjuvant treatment. Life Sci. 250: https://doi.org/10.1016/j.lfs.2020.117583.
Kleszczyński K, Slominski AT, Steinbrink K, Reiter RJ (2020) Clinical trials for use of melatonin to fight against COVID-19 are urgently needed. Nutrients 12: https://doi.org/10.3390/nu12092561.
Cardinali DP, Brown GM, Pandi-Perumal SR. (2020) Can melatonin be a potential “silver bullet” in treating COVID-19 patients? Dis. (Basel, Switzerland) 8 (4): 44. doi: 10.3390/diseases8040044
Borbély AA, Daan S, Wirz-Justice A, Deboer T (2016) The two-process model of sleep regulation: A reappraisal. J. Sleep Res. 25: 131–143. https://doi.org/10.1111/jsr.12371.
Saper CB, Fuller PM (2017) Wake–sleep circuitry: an overview. Curr. Opin. Neurobiol. 44: 186–192. https://doi.org/10.1016/j.conb.2017.03.021.
Anaclet C, Ferrari L, Arrigoni E, Bass CE, Saper CB, Lu J, et al. (2014) The GABAergic parafacial zone is a medullary slow wave sleep-promoting center. Nat. Neurosci. 17: 1217–1224. https://doi.org/10.1038/nn.3789.
Oishi Y, Xu Q, Wang L, Zhang BJ, Takahashi K, Takata Y, et al. (2017) Slow-wave sleep is controlled by a subset of nucleus accumbens core neurons in mice. Nat. Commun. 8 (1): 734. doi: 10.1038/s41467-017-00781-4.
Chung S, Weber F, Zhong P, Tan CL, Nguyen TN, Beier KT, et al. (2017) Identification of preoptic sleep neurons using retrograde labelling and gene profiling. Nature 545: 477–481. https://doi.org/10.1038/nature22350.
Kaur S, Saper CB (2019) Neural circuitry underlying waking up to hypercapnia. Front. Neurosci. 13: 401. doi: 10.3389/fnins.2019.00401.
Ono D, Mukai Y, Hung CJ, Chowdhury S, Sugiyama T, Yamanaka A (2020) The mammalian circadian pacemaker regulates wakefulness via CRF neurons in the paraventricular nucleus of the hypothalamus. Sci. Adv. 6 (45): eabd0384. doi: 10.1126/sciadv.abd0384.
Frighetto L, Marra C, Bandali S, Wilbur K, Naumann T, Jewesson P. (2004) An assessment of quality of sleep and the use drugs with sedating properties in hospitalized adult patients. Health Qual Life Outcomes 2: 17. doi: 10.1186/1477-7525-2-17.
Tamrat R, Huynh-Le MP, Goyal M (2014) Non-pharmacologic interventions to improve the sleep of hospitalized patients: A systematic review. J. Gen. Intern. Med. 29: 788–795. https://doi.org/10.1007/s11606-013-2640-9.
Southwell M, Wistow G (1995) Sleep in hospitals at night: are patients’ needs being met? J. Adv. Nurs 21: 1101–1109. https://doi.org/10.1046/j.1365-2648.1995.21061101.x.
Gay PC (2010) Sleep and sleep-disordered breathing in the hospitalized patient. Respir. Care 55: 1240–1254.
Fontana CJ, Pittiglio LI. (2010) Sleep deprivation among critical care patients. Crit. Care Nurs Q 33: 75–81. https://doi.org/10.1097/CNQ.0b013e3181c8e030.
Boyko Y, Ørding H, Jennum P (2012) Sleep disturbances in critically ill patients in ICU: How much do we know? Acta Anaesthesiol. Scand. 56: 950–958. https://doi.org/10.1111/j.1399-6576.2012.02672.x.
Kamdar BB, Needham DM, Collop NA (2012) Sleep deprivation in critical illness: Its role in physical and psychological recovery. J. Intensive Care Med. 27: 97–111. https://doi.org/10.1177/0885066610394322.
Cooke M, Ritmala-Castrén M, Dwan T, Mitchell M (2020) Effectiveness of complementary and alternative medicine interventions for sleep quality in adult intensive care patients: A systematic review. Int. J. Nurs Stud. 107: 103582. doi: 10.1016/j.ijnurstu.2020.103582.
Pisani MA, D’Ambrosio C (2020) Sleep and delirium in adults who are critically Ill: A Contemporary Review. Chest 157: 977–984. https://doi.org/10.1016/j.chest.2019.12.003.
Bertsche T, Pfaff J, Schiller P, Kaltschmidt J, Pruszydlo MG, Stremmel W, et al. (2010) Prevention of adverse drug reactions in intensive care patients by personal intervention based on an electronic clinical decision support system. Intensive Care Med. 36: 665–672. https://doi.org/10.1007/s00134-010-1778-8.
Olofsson K, Alling C, Lundberg D, Malmros C (2004) Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol. Scand. 48: 679–84. https://doi.org/10.1111/j.0001-5172.2004.00401.x.
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 77: 683. https://doi.org/10.1001/jamaneurol.2020.1127.
Salluh JIF, Wang H, Schneider EB, Nagaraja N, Yenokyan G, Damluji A, et al. (2015) Outcome of delirium in critically ill patients: Systematic review and meta-analysis. BMJ 350: 1–10. https://doi.org/10.1136/bmj.h2538.
Chellappa SL, Vujovic N, Williams JS, Scheer FAJL. Impact of circadian disruption on cardiovascular function and disease (2019) Trends Endocrinol. Metab. 30: 767–779. https://doi.org/10.1016/j.tem.2019.07.008.
Grandner MA (2020) Sleep, health, and society. Sleep Med. Clin. 15: 319–340. https://doi.org/10.1016/j.jsmc.2020.02.017.
Brownlow JA, Miller KE, Gehrman PR (2020) Insomnia and cognitive performance. Sleep Med. Clin. 15: 71–76. https://doi.org/10.1016/j.jsmc.2019.10.002.
Ferini-Strambi L, Galbiati A, Casoni F, Salsone .(2020) Therapy for insomnia and circadian rhythm disorder in Alzheimer disease. Curr. Treat. Options Neurol. 22 (2): 4. doi: 10.1007/s11940-020-0612-z.
Shilts J, Chen G, Hughey JJ (2018) Evidence for widespread dysregulation of circadian clock progression in human cancer. PeerJ 6: e4327. doi: 10.7717/peerj.4327.
Daniel LC, van Litsenburg RRL, Rogers VE, Zhou ES, Ellis SJ, Wakefield CE, et al. (2020) A call to action for expanded sleep research in pediatric oncology: A position paper on behalf of the International Psycho-Oncology Society Pediatrics Special Interest Group. Psychooncology 29: 465–474. https://doi.org/10.1002/pon.5242.
Haspel JA, Anafi R, Brown MK, Cermakian N, Depner C, Desplats P, et al. (2020) Perfect timing: Circadian rhythms, sleep, and immunity — An NIH workshop summary. JCI Insight 5 (1): e131487. doi: 10.1172/jci.insight.131487.
Emens JS, Eastman CI (2017) Diagnosis and treatment of non-24-h sleep–wake disorder in the blind. Drugs 77: 637–650. https://doi.org/10.1007/s40265-017-0707-3.
Gobbi G, Comai S (2019) Sleep well. Untangling the role of melatonin MT1 and MT2 receptors in sleep. J. Pineal Res. 66: https://doi.org/10.1111/jpi.12544.
Ibrahim MG, Bellomo R, Hart GK, Norman T, Goldsmith D, Bates S, et al. (2006) A double-blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomised patients. Crit. Care Resusc. 8: 187–191.
Bourne RS, Mills GH, Minelli C (2008) Melatonin therapy to improve nocturnal sleep in critically ill patients: Encouraging results from a small randomised controlled trial. Crit. Care 12 (2): R52. doi: 10.1186/cc6871.
Foreman B, Westwood AJ, Claassen J, Bazil CW (2015) Sleep in the neurological intensive care unit: Feasibility of quantifying sleep after melatonin supplementation with environmental light and noise reduction. J. Clin. Neurophysiol. 32: 66–74. https://doi.org/10.1097/WNP.0000000000000110.
Bellapart J, Boots R (2012) Potential use of melatonin in sleep and delirium in the critically ill. Br. J. Anaesth. 108: 572–580. https://doi.org/10.1093/bja/aes035.
Soltani F, Salari A, Javaherforooshzadeh F, Nassajjian N, Kalantari F (2020) The effect of melatonin on reduction in the need for sedative agents and duration of mechanical ventilation in traumatic intracranial hemorrhage patients: a randomized controlled trial. Eur. J. Trauma Emerg. Surg. 1-7. doi: 10.1007/s00068-020-01449-3
Mistraletti G, Umbrello M, Miori S, Taverna M, Cerri B, Mantovani E, et al. (2015) Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol. 81: 1298–1310.
Pévet P, Klosen P, Felder-Schmittbuhl MP (2017) The hormone melatonin: Animal studies. Best Pract. Res. Clin. Endocrinol. Metab. 31: 547–559. https://doi.org/10.1016/j.beem.2017.10.010.
Dawson D, Armstrong SM (1996) Chronobiotics - Drugs that shift rhythms. Pharmacol. Ther. 69: 15–36. https://doi.org/10.1016/0163-7258(95)02020-9.
Kandalepas PC, Mitchell JW, Gillette MUG (2016) Melatonin signal transduction pathways require E-Box-mediated transcription of Per1 and Per2 to reset the SCN clock at dusk. PLoS One 11 (6): e0157824. doi: 10.1371/journal.pone.0157824.
Arendt J (2019) Melatonin: countering chaotic time cues. Front. Endocrinol. (Lausanne) 10: 391. doi: 10.3389/fendo.2019.00391.
Clarke IJ, Caraty A (2013) Kisspeptin and seasonality of reproduction. Adv. Exp. Med. Biol. 784: 411–430. https://doi.org/10.1007/978-1-4614-6199-9_19.
Tan DX, Xu B, Zhou X, Reiter RJ (2018) Pineal calcification, melatonin production, aging, associated health consequences and rejuvenation of the pineal gland. Molecules 23 (2): 301. doi: 10.3390/molecules23020301
Skene DJ, Arendt J (2017) Circadian rhythm sleep disorders in the blind and their treatment with melatonin. Sleep Med. 8: 651–655. https://doi.org/10.1016/j.sleep.2006.11.013.
Lewy A (2010) Clinical implications of the melatonin phase response curve. J. Clin. Endocrinol. Metab. 95: 3158–3160. https://doi.org/10.1210/jc.2010-1031.
Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR (2011) Melatonin-A pleiotropic, orchestrating regulator molecule. Prog. Neurobiol. 93 (3): 350-384. doi: 10.1016/j.pneurobio.2010.12.004
Cardinali D (2019) Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection? Melatonin Res. 2: 106–132. https://doi.org/10.32794/mr11250025.
Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J (2010) International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol. Rev. 62 (3): 343-380. doi: 10.1124/pr.110.002832.
Cecon E, Oishi A, Jockers R (2018) Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br. J. Pharmacol. 175: 3263–3280. https://doi.org/10.1111/bph.13950.
Cardinali DP, Lynch HJ, Wurtman RJ (1972) Binding of melatonin to human and rat plasma proteins. Endocrinology 91: 1213–1218. https://doi.org/10.1210/endo-91-5-1213.
Claustrat B, Leston J (2015) Melatonin: Physiological effects in humans. Neurochirurgie 61: 77–84. https://doi.org/10.1016/j.neuchi.2015.03.002.
Acuña-Castroviejo D, Escames G, Venegas C, Díaz-Casado ME, Lima-Cabello E, López LC, et al. (2014) Extrapineal melatonin: Sources, regulation, and potential functions. Cell Mol Life Sci. 71: 2997–3025. https://doi.org/10.1007/s00018-014-1579-2.
Tan D-X, Reiter R (2019) Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells. Melatonin Res. 2: 44–66. https://doi.org/10.32794/mr11250011.
Arendt J (2018) Approaches to the pharmacological management of jet lag. Drugs 78: 1419–1431. https://doi.org/10.1007/s40265-018-0973-8.
Burgess HJ, Emens JS (2018) Drugs used in circadian sleep-wake rhythm disturbances. Sleep Med. Clin. 13: 231–241. https://doi.org/10.1016/j.jsmc.2018.02.006.
Gobbi G, Comai S (2019) Differential function of melatonin MT1 and MT2 receptors in REM and NREM sleep. Front. Endocrinol. (Lausanne) 10: 87. doi: 10.3389/fendo.2019.00087
Ferracioli-Oda E, Qawasmi A, Bloch MH (2013) Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One 8 (5): e63773. doi: 10.1371/journal.pone.0063773.
Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL (2017) Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Med. Rev. 34: 10–22. https://doi.org/10.1016/j.smrv.2016.06.005.
Li T, Jiang S, Han M, Yang Z, Lv J, Deng C, et al. (2019) Exogenous melatonin as a treatment for secondary sleep disorders: A systematic review and meta-analysis. Front Neuroendocrinol. 52: 22–28. https://doi.org/10.1016/j.yfrne.2018.06.004.
Wilson SJ, Nutt DJ, Alford C, Argyropoulos S V., Baldwin DS, Bateson AN, et al. (2010) British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J. Psychopharmacol. 24: 1577–1600. https://doi.org/10.1177/0269881110379307.
Geoffroy PA, Micoulaud Franchi JA, Lopez R, Schroder CM (2019) The use of melatonin in adult psychiatric disorders: Expert recommendations by the French Institute of Medical Research on Sleep (SFRMS). Encephale 45: 413–423. https://doi.org/10.1016/j.encep.2019.04.068.
Palagini L, Manni R, Aguglia E, Amore M, Brugnoli R, Girardi P, et al. (2020) Expert opinions and consensus recommendations for the evaluation and management of insomnia in clinical practice: joint statements of five Italian scientific societies. Front. Psychiatry 11: 558. https://doi.org/10.3389/fpsyt.2020.00558.
Vecchierini MF, Kilic-Huck U, Quera-Salva MA (2020) Melatonin (MEL) and its use in neurological diseases and insomnia: Recommendations of the French Medical and Research Sleep Society (SFRMS). Rev. Neurol. (Paris) S0035-3787 (20): 30656-1. doi: 10.1016/j.neurol.2020.06.009.
Riemersma-van Der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJG, Van Someren EJW (2008) Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: A randomized controlled trial. JAMA 299: 2642–2655. https://doi.org/10.1001/jama.299.22.2642.
Fainstein I, Bonetto AJ, Brusco LI, Cardinali DP (1997) Effects of melatonin in elderly patients with sleep disturbance: A pilot study. Curr. Ther. Res. Clin. Exp. 58: 990-1000. https://doi.org/10.1016/S0011-393X(97)80066-5.
Cardinali DP, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco LI (2012) Therapeutic application of melatonin in mild cognitive impairment. Am. J. Neurodegener Dis. 1 (3): 280-291.
Hampshire A, Trender W, Chamberlain SR, Jolly A, Grant JE, Patrick F, et al. (2020) Cognitive deficits in people who have recovered from COVID-19 relative to controls: An N=84,285 online study. MedRxiv 2020: 10.20.20215863. https://doi.org/10.1101/2020.10.20.20215863.
Raj V, Opie M, Arnold AC (2018) Cognitive and psychological issues in postural tachycardia syndrome. Auton. Neurosci. Basic. Clin. 215: 46–55. https://doi.org/10.1016/j.autneu.2018.03.004.
Wells R, Paterson F, Bacchi S, Page A, Baumert M, Lau DH (2020) Brain fog in postural tachycardia syndrome: An objective cerebral blood flow and neurocognitive analysis. J. Arrhythmia 36: 549–552. https://doi.org/10.1002/joa3.12325.
Cardinali DP (2019) Melatonin: Clinical perspectives in neurodegeneration. Front. Endocrinol. (Lausanne) 10: 480. https://doi.org/10.3389/fendo.2019.00480.
Acuña-Castroviejo D, Escames G, Figueira JC, de la Oliva P, Borobia AM, Acuña-Fernández C (2020) Clinical trial to test the efficacy of melatonin in COVID-19. J. Pineal Res. 69 (3):e12683. doi: 10.1111/jpi.12683.
Artigas L, Coma M, Matos-Filipe P, Aguirre-Plans J, Farrés J, Valls R, et al. (2020) In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm. PLoS One 15 (10): e0240149. doi: 10.1371/journal.pone.0240149.
Cardinali DP. High doses of melatonin as a potential therapeutic tool for the neurologic sequels of COVID-19 infection (2020) Melatonin Res. 3: 311–317. https://doi.org/10.32794/mr11250064.
Simko F, Hrenak J, Dominguez-Rodriguez A, Reiter RJ (2020) Melatonin as a putative protection against myocardial injury in COVID-19 infection. Expert Rev. Clin. Pharmacol. 13 (9): 921-924. doi: 10.1080/17512433.2020.1814141.
Reiter RJ, Sharma R, Ma Q, Dominquez-Rodriguez A, Marik PE, Abreu-Gonzalez P (2020) Melatonin inhibits COVID-19-induced cytokine storm by reversing aerobic glycolysis in immune cells: a mechanistic analysis. Med. Drug Discov. 6: 100044. https://doi.org/10.1016/j.medidd.2020.100044.
Pandi-Perumal SR, Cardinali DP, Reiter RJ, Brown GM (2020) Low melatonin as a contributor to SARS-CoV-2 disease. Melatonin Res. 3: 558–76. https://doi.org/10.32794/mr11250079.
Ueland T, Holter JC, Holten AR, Müller KE, Lind A, Bekken GK, et al. (2020) Distinct and early increase in circulating MMP-9 in COVID-19 patients with respiratory failure: MMP-9 and respiratory failure in COVID-19. J. Infect. 81: e41–e43. https://doi.org/10.1016/j.jinf.2020.06.061.
Hazra S, Chaudhuri AG, Tiwary BK, Chakrabarti N (2020) Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis. Life Sci. 257:118096. doi: 10.1016/j.lfs.2020.118096.
Tesarik J (2020) Melatonin attenuates growth factor receptor signaling required for SARS-CoV-2 replication. Melatonin Res. 3: 534–537. https://doi.org/10.32794/mr11250077.
Bazyar H, Gholinezhad H, Moradi L, Salehi P, Abadi F, Ravanbakhsh M, et al. (2019) The effects of melatonin supplementation in adjunct with non-surgical periodontal therapy on periodontal status, serum melatonin and inflammatory markers in type 2 diabetes mellitus patients with chronic periodontitis: a double-blind, placebo-controlled trial. Inflammopharmacology 27: 67–76. https://doi.org/10.1007/s10787-018-0539-0.
Sánchez-López AL, Ortiz GG, Pacheco-Moises FP, Mireles-Ramírez MA, Bitzer-Quintero OK, Delgado-Lara DLC, et al. (2018) Efficacy of Melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing remitting multiple sclerosis. Arch. Med. Res. 49: 391–398. https://doi.org/10.1016/j.arcmed.2018.12.004.
Kücükakin B, Lykkesfeldt J, Nielsen HJ, Reiter RJ, Rosenberg J, Gögenur I (2018) Utility of melatonin to treat surgical stress after major vascular surgery - A safety study. J. Pineal Res. 44: 426–431. https://doi.org/10.1111/j.1600-079X.2007.00545.x.
Zhao Z, Lu C, Li T, Wang W, Ye W, Zeng R, et al. (2018) The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: In vivo assessment and a randomized controlled trial. J. Pineal Res. 65: https://doi.org/10.1111/jpi.12521.
Shafiei E, Bahtoei M, Raj P, Ostovar A, Iranpour D, Akbarzadeh S, et al. (2018) Effects of N-acetyl cysteine and melatonin on early reperfusion injury in patients undergoing coronary artery bypass grafting: A randomized, open-labeled, placebo-controlled trial. Med. (United States) 97 (30): e11383 doi.org/10.1097/MD.0000000000011383.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. (2020) Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 395: 507–513. https://doi.org/10.1016/S0140-6736(20)30211-7.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395: 497–506. https://doi.org/10.1016/S0140-6736(20)30183-5.
Volt H, García JA, Doerrier C, Díaz-Casado ME, Guerra-Librero A, Lõpez LC, et al. (2016) Same molecule but different expression: Aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. J.. Pineal Res. 60: 193–205. https://doi.org/10.1111/jpi.12303.
Dai W, Huang H, Si L, Hu S, Zhou L, Xu L, et al. (2019) Melatonin prevents sepsis-induced renal injury via the PINK1/Parkin1 signaling pathway. Int. J. Mol. Med. 44: 1197–1204. https://doi.org/10.3892/ijmm.2019.4306.
Zhang J, Wang L, Xie W, Hu S, Zhou H, Zhu P, et al. (2020) Melatonin attenuates ER stress and mitochondrial damage in septic cardiomyopathy: A new mechanism involving BAP31 upregulation and MAPK-ERK pathway. J. Cell Physiol. 235: 2847–2856. https://doi.org/10.1002/jcp.29190.
Chen J, Xia H, Zhang L, Zhang H, Wang D, Tao X (2019) Protective effects of melatonin on sepsis-induced liver injury and dysregulation of gluconeogenesis in rats through activating SIRT1/STAT3 pathway. Biomed. Pharmacother 117: 109150. doi.org/10.1016/j.biopha.2019.109150.
Lewandowska K, Małkiewicz MA, Siemiński M, Cubała WJ, Winklewski PJ, Mędrzycka-Dąbrowska WA. (2020) The role of melatonin and melatonin receptor agonist in the prevention of sleep disturbances and delirium in intensive care unit – a clinical review. Sleep Med. 69: 127–134. https://doi.org/10.1016/j.sleep.2020.01.019.
Castillo RR, Quizon GRA, Juco MJM, Roman ADE, De Leon DG, Punzalan FER, et al. (2020) Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series. Melatonin Res. 3: 297–310. https://doi.org/10.32794/mr11250063.
Ramlall V, Zucker J, Tatonetti N (2020) Melatonin is significantly associated with survival of intubated COVID-19 patients. MedRxiv Prepr. Serv. Heal Sci. 2020: https://doi.org/10.1101/2020.10.15.20213546.
Cooper KR, Phillips BA (1982) Effect of short-term sleep loss on breathing. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 53: 855–858. https://doi.org/10.1152/jappl.1982.53.4.855.
Shilo L, Dagan Y, Smorjik Y, Weinberg U, Dolev S, Komptel B, et al. (2000) Effect of melatonin on sleep quality of COPD intensive care patients: A pilot study. Chronobiol. Int. 17: 71–76. https://doi.org/10.1081/CBI-100101033.
Majmundar M, Kansara T, Lenik JM, Park H, Ghosh K, Doshi R, et al. (2020) Efficacy of corticosteroids in non-intensive care unit patients with COVID-19 pneumonia from the New York Metropolitan region. PLoS One 15 (9): e0238827 doi.org/10.1371/journal.pone.0238827.
Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14: 135. doi: 10.1186/1471-2288-14-135.
Reiter RJ, Abreu-Gonzalez P, Marik PE, Dominguez-Rodriguez A. (2020) Therapeutic algorithm for use of melatonin in patients with COVID-19. Front. Med. 7: 226. https://doi.org/10.3389/fmed.2020.00226.
Besag FMC, Vasey MJ, Lao KSJ, Wong ICK (2019) Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: a systematic review. CNS Drugs 33: 1167–1186. https://doi.org/10.1007/s40263-019-00680-w.
Andersen LPH, Gögenur I, Rosenberg J, Reiter RJ (2016) the safety of melatonin in humans. Clin. Drug Investig. 36: 169–175. https://doi.org/10.1007/s40261-015-0368-5.
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