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1.
Factors Disrupting Melatonin Secretion Rhythms During Critical Illness.
Maas, MB, Lizza, BD, Abbott, SM, Liotta, EM, Gendy, M, Eed, J, Naidech, AM, Reid, KJ, Zee, PC
Critical care medicine. 2020;(6):854-861
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Abstract
OBJECTIVES The circadian system modulates many important physiologic processes, synchronizing tissue-specific functions throughout the body. We sought to characterize acute alterations of circadian rhythms in critically ill patients and to evaluate associations between brain dysfunction, systemic multiple organ dysfunction, environmental stimuli that entrain the circadian rhythm (zeitgebers), rest-activity rhythms, and the central circadian rhythm-controlled melatonin secretion profile. DESIGN Prospective study observing a cohort for 24-48 hours beginning within the first day of ICU admission. SETTING Multiple specialized ICUs within an academic medical center. PATIENTS Patients presenting from the community with acute onset of either intracerebral hemorrhage as a representative neurologic critical illness or sepsis as a representative systemic critical illness. Healthy control patients were studied in using modified constant routine in a clinical research unit. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Light, feeding, activity, medications, and other treatment exposures were evaluated along with validated measures of encephalopathy (Glasgow Coma Scale), multiple organ system function (Sequential Organ Failure Assessment score), and circadian rhythms (profiles of serum melatonin and its urinary metabolite 6-sulphatoxymelatonin). We studied 112 critically ill patients, including 53 with sepsis and 59 with intracerebral hemorrhage. Environmental exposures were abnormal, including light (dim), nutritional intake (reduced or absent and mistimed), and arousal stimuli (increased and mistimed). Melatonin amplitude and acrophase timing were generally preserved in awake patients but dampened and delayed with increasing encephalopathy severity. Melatonin hypersecretion was observed in patients exposed to catecholamine vasopressor infusions, but unaffected by sedatives. Change in vasopressor exposure was the only factor associated with changes in melatonin rhythms between days 1 and 2. CONCLUSIONS Encephalopathy severity and adrenergic agonist medication exposure were the primary factors contributing to abnormal melatonin rhythms. Improvements in encephalopathy and medical stabilization did not rapidly normalize rhythms. Urinary 6-sulphatoxymelatonin is not a reliable measure of the central circadian rhythm in critically ill patients.
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The association between melatonin and episodic migraine: A pilot network meta-analysis of randomized controlled trials to compare the prophylactic effects with exogenous melatonin supplementation and pharmacotherapy.
Tseng, PT, Yang, CP, Su, KP, Chen, TY, Wu, YC, Tu, YK, Lin, PY, Stubbs, B, Carvalho, AF, Matsuoka, YJ, et al
Journal of pineal research. 2020;(2):e12663
Abstract
Although exogenous melatonin supplementation has been suggested to be effective for episodic migraine prophylaxis, there is no conclusive evidence comparing the efficacy of exogenous melatonin supplementation to the other FDA-approved pharmacotherapy for episodic migraine prophylaxis. The aim of the current network meta-analysis (NMA) was to compare the efficacy of exogenous melatonin supplementation in patients with episodic migraine. The randomized placebo-controlled trials or randomized controlled trials (RCTs) incorporating a placebo in the study designs were included in our analyses. All of the NMA procedures were conducted under the frequentist model. The primary outcome was changes in frequency of migraine days and response rate after migraine prophylaxis with melatonin supplementation or pharmacological interventions. We included 25 RCTs in total with 4499 patients (mean age = 36.0 years, mean female proportion = 78.9%). The NMA demonstrated that migraine prophylaxis with oral melatonin 3 mg/d (immediate-release) at bedtime was associated with the greatest improvement in migraine frequency [mean difference = -1.71 days, 95% confidence interval (CI): -3.27 to -0.14 days compared to placebo] and the second highest response rate (odds ratio = 4.19, 95% CI = 1.46 to 12.00 compared to placebo). Furthermore, oral melatonin 3 mg (immediate-release) at bedtime was the most preferred pharmacological intervention among all of the investigated interventions when improvements in migraine frequency, response rate, dropout rate, and rates of any adverse events were taken into account. This pilot NMA suggests the potential prophylactic role of exogenous melatonin supplementation in patients with episodic migraine.
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Melatonin supplementation and the effects on clinical and metabolic status in Parkinson's disease: A randomized, double-blind, placebo-controlled trial.
Daneshvar Kakhaki, R, Ostadmohammadi, V, Kouchaki, E, Aghadavod, E, Bahmani, F, Tamtaji, OR, J Reiter, R, Mansournia, MA, Asemi, Z
Clinical neurology and neurosurgery. 2020;:105878
Abstract
OBJECTIVE This study was performed to evaluate the impact of melatonin supplementation on clinical and metabolic profiles in people with Parkinson's disease (PD). METHODS This randomized, double-blind, placebo-controlled clinical trial was conducted among 60 patients with PD. Participants were randomly divided into two groups to intake either 10 mg melatonin (two melatonin capsules, 5 mg each) (n = 30) or placebo (n = 30) once a day, 1 h before bedtime for 12 weeks. RESULTS Melatonin supplementation significantly reduced the Unified Parkinson's Disease Rating Scale (UPDRS) part I score (β -2.33; 95% CI, -3.57, -1.09; P < 0.001), Pittsburgh Sleep Quality Index (PSQI) (β -1.82; 95% CI, -3.36, -0.27; P = 0.02), Beck Depression Inventory (BDI) (β -3.32; 95% CI, -5.23, -1.41; P = 0.001) and Beck Anxiety Inventory (BAI) (β -2.22; 95% CI, -3.84, -0.60; P = 0.008) compared with the placebo treatment. Compared with the placebo, melatonin supplementation resulted in a significant reduction in serum high sensitivity C-reactive protein (hs-CRP) (β -0.94 mg/L; 95% CI, -1.55, -0.32; P = 0.003) and a significant elevation in plasma total antioxidant capacity (TAC) (β 108.09 mmol/L; 95% CI, 78.21, 137.97; P < 0.001) and total glutathione (GSH) levels (β 77.08 μmol/L; 95% CI, 44.29, 109.86; P < 0.001). Additionally, consuming melatonin significantly decreased serum insulin levels (β -1.79 μIU/mL; 95% CI, -3.12, -0.46; P = 0.009), homeostasis model of assessment-insulin resistance (HOMA-IR) (β -0.47; 95% CI, -0.80, -0.13; P = 0.007), total- (β -13.16 mg/dL; 95% CI, -25.14, -1.17; P = 0.03) and LDL- (β -10.44 mg/dL; 95% CI, -20.55, -0.34; P = 0.04) compared with the placebo. CONCLUSIONS Overall, melatonin supplementation for 12 weeks to patients with PD had favorable effects on the UPDRS part I score, PSQI, BDI, BAI, hs-CRP, TAC, GSH, insulin levels, HOMA-IR, total-, LDL-cholesterol, and gene expression of TNF-α, PPAR-γ and LDLR, but did not affect other metabolic profiles.
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Melatonin Content of Human Milk: The Effect of Mode of Delivery.
Aparici-Gonzalo, S, Carrasco-García, Á, Gombert, M, Carrasco-Luna, J, Pin-Arboledas, G, Codoñer-Franch, P
Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine. 2020;(9):589-594
Abstract
Objective: Cesarean section rates are increasing in developed countries and could be performed as an emergency or elective procedure. Our research aim was to determine whether elective cesarean section influences the melatonin content, the main circadian hormone, in human milk. Methods: Twenty-one women after vaginal delivery and 18 women after elective cesarean section were included. Only healthy mothers with normal newborns exclusively breastfed were recruited. Two samples of human milk were collected for each woman at three stages of lactation: colostrum, transitional milk, and mature milk; at each stage, one daytime sample and another nighttime sample were obtained. In total, 228 milk samples were studied. The melatonin content was analyzed by enzyme-linked immunosorbent assay. Results: Melatonin rhythmicity with higher melatonin content at night was maintained at each of the three stages of lactation, regardless of the type of delivery. A higher melatonin content was found in daytime colostrum after cesarean section with respect to colostrum obtained from mothers after vaginal delivery (30.3 pg/mL versus 14.7 pg/mL, p = 0.020). Melatonin content decreased progressively throughout the course of lactation in both groups. This decrease was significant when comparing transitional milk to colostrum in the cesarean group, both in the daytime (p = 0.016) and nighttime samples (p = 0.048). Conclusions: Cesarean section is associated with an increase in daytime colostrum melatonin. No difference was observed in mature milk with respect to vaginal delivery. Melatonin values in human milk decrease during the first month of lactation and circadian rhythmicity was observed irrespective of the mode of delivery.
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Clinical Trials for Use of Melatonin to Fight against COVID-19 Are Urgently Needed.
Kleszczyński, K, Slominski, AT, Steinbrink, K, Reiter, RJ
Nutrients. 2020;(9)
Abstract
The recent pandemic of COVID-19 has already infected millions of individuals and has resulted in the death of hundreds of thousands worldwide. Based on clinical features, pathology, and the pathogenesis of respiratory disorders induced by this and other highly homogenous coronaviruses, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response contribute to COVID-19 pathology; these are caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This leads to a cytokine storm and subsequent progression triggering acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and often death. We and others have reported melatonin to be an anti-inflammatory and anti-oxidative molecule with a high safety profile. It is effective in critical care patients by reducing their vascular permeability and anxiety, inducing sedation, and improving their quality of sleep. As melatonin shows no harmful adverse effects in humans, it is imperative to introduce this indoleamine into clinical trials where it might be beneficial for better clinical outcomes as an adjuvant treatment of COVID-19-infected patients. Herein, we strongly encourage health care professionals to test the potential of melatonin for targeting the COVID-19 pandemic. This is urgent, since there is no reliable treatment for this devastating disease.
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Melatonin daily oral supplementation attenuates inflammation and oxidative stress in testes of men with altered spermatogenesis of unknown aetiology.
Riviere, E, Rossi, SP, Tavalieri, YE, Muñoz de Toro, MM, Ponzio, R, Puigdomenech, E, Levalle, O, Martinez, G, Terradas, C, Calandra, RS, et al
Molecular and cellular endocrinology. 2020;:110889
Abstract
We have previously shown an inverse correlation between testicular melatonin concentration and inflammation/oxidative stress-related markers levels in infertile men showing unexplained azoospermia. Here, we evaluated the impact of melatonin oral supplementation (daily 3 mg dose used to treat sleep disorders) in the incidence of local inflammation, oxidative stress, and tubular wall fibrosis development in young and middle-aged infertile adult men. Compared with testes without histological alterations, gonads with morphological abnormalities showed lower melatonin concentration along with increased macrophage numbers, TBARS generation, and expression levels of inflammation-related markers and antioxidant enzymes, as well as tubular wall collagen fibers disorganization and thickening. Melatonin oral supplementation not only increased its own testicular levels but also decreased inflammation- and oxidative stress-related markers levels, and improved the tubular wall aspect. Overall, our work provides insights into the potential benefits of melatonin on the inflammatory and oxidative status in testes of patients suffering from unexplained infertility.
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Integrative considerations during the COVID-19 pandemic.
Alschuler, L, Weil, A, Horwitz, R, Stamets, P, Chiasson, AM, Crocker, R, Maizes, V
Explore (New York, N.Y.). 2020;(6):354-356
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Melatonin Use in Hospitalized Children for Non-Anesthetic Indications: A Systematic Review.
Procaccini, DE, Lobner, K, Anton, B, Kudchadkar, SR
Pharmacotherapy. 2020;(7):692-703
Abstract
Melatonin, a potent free radical scavenger, plays an important role in homeostasis of cell and organ physiology. The increased demand and synthesis from the pineal gland during times of oxidative stress suggests a potential benefit of melatonin supplementation during hospitalization for acute illness. Yet, the paucity of clinical studies for non-anesthetic-associated indications in pediatric populations hampers the safe, effective, and consistent use of melatonin. The objective of this study was to systematically review published studies of melatonin use for non-sedative and non-analgesic indications in hospitalized pediatric patients. We conducted a search of PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Scopus databases for articles on the use of melatonin for pediatric patients in a hospital setting. Thirteen eligible studies, all in neonates, were identified. Data elements extracted included study design, number of study subjects, indication for melatonin therapy, and melatonin regimen (formulation, dosage, and duration). Because study methodologies were very heterogeneous, a quantitative synthesis of the published findings was not possible. The identified studies were therefore categorized by the indication of melatonin (adjuvant-antioxidant or anti-inflammatory therapy) in the following specific disease states: (i) acute infections, (ii) respiratory distress syndrome, (iii) neurologic injury, and (iv) jaundice. The current data suggest that melatonin is safe for use in hospitalized neonates. Melatonin may be beneficial for reducing inflammatory markers in neonatal patients with disease states and clinical sequelae that are associated with increased inflammation and oxidative stress. Melatonin, in conjunction with phototherapy, is not superior to use of vitamin D with phototherapy for treatment of neonatal jaundice. However, studies in other pediatric populations are needed given widespread use across clinical inpatient settings.
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Effect of diurnal intermittent fasting during Ramadan on ghrelin, leptin, melatonin, and cortisol levels among overweight and obese subjects: A prospective observational study.
Al-Rawi, N, Madkour, M, Jahrami, H, Salahat, D, Alhasan, F, BaHammam, A, Al-Islam Faris, M
PloS one. 2020;(8):e0237922
Abstract
BACKGROUND Levels of cortisol, melatonin, ghrelin, and leptin are highly correlated with circadian rhythmicity. The levels of these hormones are affected by sleep, feeding, and general behaviors, and fluctuate with light and dark cycles. During the fasting month of Ramadan, a shift to nighttime eating is expected to affect circadian rhythm hormones and, subsequently, the levels of melatonin, cortisol, ghrelin, and leptin. The present study aimed to examine the effect of diurnal intermittent fasting (DIF) during Ramadan on daytime levels of ghrelin, leptin, melatonin, and cortisol hormones in a group of overweight and obese subjects, and to determine how anthropometric, dietary, and lifestyle changes during the month of Ramadan correlate with these hormonal changes. METHODS Fifty-seven overweight and obese male (40) and female (17) subjects were enrolled in this study. Anthropometric measurements, dietary intake, sleep duration, and hormonal levels of serum ghrelin, leptin, melatonin, and salivary cortisol were assessed one week before the start of Ramadan fasting and after 28 days of fasting at fixed times of the day (11:00 am-1:00 pm). RESULTS At the end of Ramadan, serum levels of ghrelin, melatonin, and leptin significantly (P<0.001) decreased, while salivary cortisol did not change compared to the levels assessed in the pre-fasting state. CONCLUSIONS DIF during Ramadan significantly altered serum levels of ghrelin, melatonin, and serum leptin. Further, male sex and anthropometric variables were the most impacting factors on the tested four hormones. Further studies are needed to assess DIF's impact on the circadian rhythmicity of overweight and obese fasting people.
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The effect of melatonin supplementation on liver indices in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized clinical trials.
Mansoori, A, Salimi, Z, Hosseini, SA, Hormoznejad, R, Jafarirad, S, Bahrami, M, Asadi, M
Complementary therapies in medicine. 2020;:102398
Abstract
Several randomized clinical trials (RCTs) evaluated the effect of melatonin supplementation on liver enzymes in patients with non-alcoholic fatty liver disease (NAFLD) and reported conflicting results. To meet these discrepancies, a meta-analysis was conducted to evaluate the eff ;ect of melatonin on liver indices in patients with NAFLD. To collect the required data, a thorough search was conducted through Web of science, Pubmed, Cochrane database, Embase, Google Scholar, ProQuest, and Scopus databases. The aim was to find clinical trials over the effect of melatonin supplementation on liver indices up to 16 May 2019. As a result, five eligible articles were selected and analysed in this meta-analysis using a fixed-effects model. Heterogeneity test was performed by I2 statistics and Cochrane Q test. The results showed that melatonin had a significant effect on aspartate aminoteransferase (AST) (WMD = 2.29, [95 %CI: 1.14, 3.43] IU/L, p = <0.001), alkaline phosphatase (ALP) (WMD = -8.40, [95 %CI -11.33, -5.48] IU/L, p < 0.001), and gamma-glutamyltransferase (GGT) (WMD = -33.37, [95 %CI: -37.24, -29.49] IU/L, p= < 0.001). Melatonin had no significant effect on alanine aminotransferase (ALT) regarding the overall effect size. Based on this meta-analysis, melatonin supplementation can improve liver indices. However, more RCTs are required with larger sample sizes and better control of confounding variables such as weight, body mass index, and gender to determine the effect of melatonin on patients with non-alcoholic fatty acid disease.