Beneficial effect of melatonin in the treatment of neonatal sepsis

El-Gendy, Fady M; El-Hawy, Mahmoud A.; Hassan, Mohamed

doi:10.1080/14767058.2017.1342794

Cited by 37 publications

(23 citation statements)

References 22 publications

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“…The increased melatonin levels are compatible with the reported disruption of circadian rhythmicity in critically ill patients [29]. Melatonin is used as a supporting drug in septic infants and could be a promising therapeutic option in sepsis patients to promote stable circadian rhythms, improve immunity and outcomes [30]. However, further research is needed to analyze the impact of the circadian rhythm on sepsis mortality and its translational potential to nd promising treatment options for improving sepsis care [31].…”

Section: Discussionmentioning

confidence: 63%

Circadian Rhythms in Septic Shock Patients

Lachmann

Ananthasubramaniam

Wünsch

et al. 2020

Preprint

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Background: Although intensive efforts to improve diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate whether the rhythmicity of clock gene expression is altered in patients with septic shock.Methods: This prospective pilot study was performed at the university hospital Charité – Universitätsmedizin Berlin, Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK). We included 20 patients with septic shock between May 2014 and January 2018, from whom blood was drawn every 4 hours over a 24-hour period to isolate CD14-positive monocytes and to measure expression of 17 clock and clock-associated genes. Of these patients, 3 whose samples expressed fewer than 8 clock genes were excluded from the final analysis. Expression data were compared to data of a healthy study population and a rhythmicity score SP was calculated, which comprises values between -1 (arrhythmic) and 1 (rhythmic). Results: Overall, the rhythmicity scores for septic shock patients were significantly (p < 0.0001) lower (0.23 ± 0.26) compared to the control group (12 healthy young men, 0.70 ± 0.18). 77% of the measured clock genes were classified as having inconclusive rhythms, i.e. neither rhythmic nor arrhythmic. The clock genes NR1D1, NR1D2 and CRY2 were the most rhythmic, while CLOCK and ARNTL were the least rhythmic. In addition, the expression of clock genes CRY1, NR1D1, NR1D2, DBP, and PER2 was suppressed in septic shock patients and CRY2 was significantly upregulated compared to controls.Conclusion: Compared to young healthy men, molecular rhythms in immune cells of septic shock patients were substantially decreased. The decrease in rhythmicity was clock gene-dependent. The loss of rhythmicity and downregulation of clock gene expression might be caused by sepsis and might further deteriorate immune responses and organ injury, but further studies are necessary to understand underlying pathophysiological mechanisms.Clinical trial registered with www.ClinicalTrials.gov (NCT02044575) on 24 January 2014.

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Section: Discussionmentioning

confidence: 63%

Circadian Rhythms in Septic Shock Patients

Lachmann

Ananthasubramaniam

Wünsch

et al. 2020

Preprint

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“…If we convert this murine dose to the human dose according to standard dose translation, based on dividing the surface area by a factor 12.3 (120), the calculated equivalent human dose is 8.1 mg/kg/day (100/12.3 = 8.1). This dose is very similar to the dose used in two neonatal septic trials (8.1 and 8.2 mg/kg/day), as described previously [86,87]. Importantly, this dose would not cause obvious adverse effects, based on the outcomes of these clinical trials.…”

Section: Melatonin and Its Safetymentioning

confidence: 73%

Clinical Trials for Use of Melatonin to Fight against COVID-19 Are Urgently Needed

et al. 2020

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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 has a robust antioxidant or free radical scavenging activity of [ 57 , 58 ] and melatonin administration also impairs NF-κB transcriptional activity, reducing pro-inflammatory cytokine (IL-1β, TNF-α, IFN-γ) release and inhibiting activation of the NLRP3 inflammasome [ 59 ]. Melatonin improved survival and clinical outcomes in neonates versus controls in sepsis [ 28 , 60 , 61 ]. We have demonstrated that the immunomodulatory effects of melatonin in sepsis can also be broadened to include reducing neutrophil and monocyte activation.…”

Section: Discussionmentioning

confidence: 99%

Altered endotoxin responsiveness in healthy children with Down syndrome

et al. 2018

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BackgroundDown syndrome (DS) is the most common syndromic immunodeficiency with an increased risk of infection, mortality from sepsis, and autoinflammation. Innate immune function is altered in DS and therefore we examined responses in CD11b and Toll like receptor 4 (TLR-4), which are important immune cell surface markers upregulated in response to Lipopolysaccharide (LPS) endotoxin, and the immunomodulator melatonin. Neutrophil and monocyte responses to LPS and melatonin in children with Down syndrome (DS) who were clinically stable were compared to age-matched controls. Whole blood was incubated with LPS and melatonin and the relative expression of CD11b and TLR-4 evaluated by flow cytometry.ResultsChildren with DS had an increased response to LPS in neutrophils and intermediate monocytes, while also having elevated TLR-4 expression on non-classical monocytes compared to controls at baseline. Melatonin reduced CD11b expression on neutrophils, total monocytes, both classical and intermediate sub-types, in children with DS and controls.ConclusionMelatonin could represent a useful clinical adjunct in the treatment of sepsis as an immunomodulator. Children with DS had increased LPS responses which may contribute to the more adverse outcomes seen in sepsis.

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Beneficial effect of melatonin in the treatment of neonatal sepsis

Abstract: Melatonin could be used in the treatment of neonatal sepsis in both preterm and full-term neonates beside the conventional treatment.

Cited by 37 publications

References 22 publications

Circadian Rhythms in Septic Shock Patients

Circadian Rhythms in Septic Shock Patients

Clinical Trials for Use of Melatonin to Fight against COVID-19 Are Urgently Needed

Altered endotoxin responsiveness in healthy children with Down syndrome

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