Search

Copyright of Journal of Inonu University Health Services Vocational School / Inönü Üniversitesi Sağlık Hizmetleri Meslek Yüksekokulu Dergisi is the property of Inonu Universitesi Saglik Hizmetleri Meslek Yuksekokulu and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Despite advancement in anti‐seizure medications, 30% of patients continue to experience recurrent seizures. Previous data indicated the antiepileptic properties of melatonin and its agonists in several animal models. However, the underlying mechanisms of melatonin and its agonists on cellular excitability remain poorly understood. In this study, we demonstrated the electrophysiological changes of two main kinds of ion channels that are responsible for hyperexcitability of neurons after introduction of melatonin agonists‐ ramelteon (RAM). In Neuro‐2a cells, the amplitude of voltage‐gated Na+ (INa) and delayed‐rectifier K+ currents (IK (DR)) could be suppressed under RAM. The IC50 values of 8.7 and 2.9 μM, respectively. RAM also diminished the magnitude of window Na+ current (INa (W)) elicited by short ascending ramp voltage, with unchanged the overall steady‐state current–voltage relationship. The decaying time course of INa during a train of depolarizing pulses arose upon the exposure to RAM. The conditioning train protocol which blocked INa fitted the recovery time course into two exponential processes and increased the fast and slow time constant of recovery the presence of RAM. In pituitary tumor (GH3) cells, INa amplitude was also effectively suppressed by the RAM. In addition, GH3‐cells exposure to RAM decreased the firing frequency of spontaneous action potentials observed under current‐clamp conditions. As a result, the RAM‐mediated effect on INa was closely associated with its ability to decrease spontaneous action potentials. Collectively, we found the direct attenuation of INa and IK (DR) caused by RAM besides the agonistic action on melatonin receptors, which could partially explain its anti‐seizure activity. [ABSTRACT FROM AUTHOR]

Psoriasis is a long-lasting, immune-related inflammatory skin disease that affects 2–3% of the global population. It is distinguished by erythematous, silvery, and scaly patches. Ramelteon is a type of melatonin agonist that is used to treat insomnia. It has enhanced non-classical immunomodulatory and anti-inflammatory activities. The aim of the study is to assess the ameliorative effects of topical ramelteon on imiquimod (IMQ)-aggravated psoriasiform-like dermatosis in mice. The 32 albino mouse males were placed into six groups of eight animals, all of them. With the exception of the control group, all groups gained a once-a-day regimen of topical imiquimod 5% cream at a dose of 62.5 mg for eight uninterrupted days, while mice in the control group gained vaseline-based ointment alternately. Immediately after an 8-day induction period in the imiquimod group, mice in the clobetasol and ramelteon treatment groups obtained a twice-daily regimen of topical clobetasol propionate 0.05% ointment and 0.1% ointment, respectively, for a further 8 days. This extends the total duration of the experimental study to 16 continuous days. The findings of our study found that ramelteon significantly mitigated the concentrations of inflammatory cytokines in the skin tissue, including interleukin (IL)-6, IL-17A, IL-23, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF), as well as the scores associated with psoriatic lesions, including erythema, scaling, skin thickening, ear thickness, and overall cumulative PASI scores. Additionally, the anti-inflammatory impact of ramelteon was achieved by markedly increasing IL-10 levels in the skin tissue and correcting cutaneous histopathological alterations. Ramelteon ointment (0.1%) was comparable to that of clobetasol (0.05%) ointment in alleviating a mouse model of imiquimod-induced psoriasiform inflammation; this is probably due to its potential anti-inflammatory and immunomodulatory activities. Therefore, ramelteon could be a good additive option for therapeutic management of immune-triggered inflammatory conditions such as psoriasis. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is a devastating lung disease that leads to impaired lung function and ultimately death. Several studies have suggested that melatonin, a hormone involved in regulating sleep–wake cycles, may be effective in improving PF. Ramelteon, an FDA-approved melatonin receptor agonist, has shown promise in exerting an anti-PF effect similar to melatonin. However, further investigations are required for illuminating the extent on its therapeutic benefits and the underlying molecular mechanisms. In this work, a mouse lung fibrosis model was built through intratracheal administration of bleomycin (BLM). Subsequently, the mice were administrated Ramelteon for a duration of 3 weeks to explore its efficacy and mechanism of action. Additionally, we utilized a TGF-β1-induced MRC-5 cell model to further investigate the molecular mechanism underlying ramelteon's effects. Functionally, Ramelteon partially abrogated TGF-β1-induced pulmonary fibrosis and reduced fibroblast proliferation, extracellular matrix deposition, and differentiation into myofibroblasts. In vivo experiments, ramelteon attenuated BLM-induced pulmonary fibrosis and collagen deposition. Mechanistically, ramelteon exerts its beneficial effect by alleviating translocation and expression of YAP1, a core component of Hippo pathway, from cytoplasm to nucleus; however, overexpression of YAP1 reversed this effect. In conclusion, our findings indicate that ramelteon can improve PF by regulating Hippo pathway and may become a potential candidate as a therapy to PF. [ABSTRACT FROM AUTHOR]

Introduction: For patients with chronic insomnia, conventional therapy may not always provide satisfactory efficacy and safety. Thus, switching to an alternative therapeutic agent can be explored. However, there is a lack of prospective studies evaluating the effectiveness of such changes. This prospective, non-randomized, open-label, interventional, multicenter study assessed whether Japanese patients with chronic insomnia dissatisfied with treatment could transition directly to lemborexant (LEM) from four cohorts—non-benzodiazepine sedative-hypnotic (zolpidem, zopiclone, or eszopiclone) monotherapy, dual orexin receptor antagonist (suvorexant) monotherapy, suvorexant + benzodiazepine receptor agonists (BZRAs), and melatonin receptor agonist (ramelteon) combination. We evaluated whether transitioning to LEM improved patient satisfaction based on efficacy and safety. Methods: The primary endpoint was the proportion of successful transitions to LEM at 2 weeks (titration phase end), defined as the proportion of patients on LEM by the end of the 2-week titration phase who were willing to continue on LEM during the maintenance phase (Weeks 2–14). Patient satisfaction and safety (the incidence of treatment-emergent adverse events [TEAEs]) were assessed at 14 weeks (end of titration and maintenance phases). Results: Among the 90 patients enrolled, 95.6% (95% confidence interval: 89.0–98.8%) successfully transitioned to LEM at 2 weeks. The proportions of patients who successfully continued on LEM were 97.8% and 82.2% at the end of the titration and maintenance phases (Weeks 2 and 14), respectively. The overall incidence of TEAEs was 47.8%; no serious TEAEs occurred. In all cohorts, the proportions of patients with positive responses were higher than the proportions with negative responses on the three scales of the Patient Global Impression-Insomnia version. During the maintenance phase, Insomnia Severity Index scores generally improved at Weeks 2, 6, and 14 of LEM transition. Conclusions: Direct transition to LEM may be a valid treatment option for patients with insomnia who are dissatisfied with current treatment. Trial Registration: ClinicalTrials.gov identifier, NCT04742699. [ABSTRACT FROM AUTHOR]

The pineal product melatonin (MEL) modulates blood vessels through G protein-coupled receptors (GPCRs) called melatonin type 1 receptor (MT1R) and melatonin type 2 receptor (MT2R), in that order. The renin-angiotensin system (RAS), which breaks down angiotensin II (Ang II) to create Ang 1–7, is thought to be mostly controlled by angiotensin-converting enzyme-2 (ACE2). The current work examines the involvement of ACE2 inhibitor, MEL, and ramelteon (RAM) in the vascular response to Ang II activities in the endothelial denuded (E-) and intact (E+) rat isolated thoracic aortic rings. The isometric tension was measured to evaluate the vascular Ang II contractility using dose response curve (DRC). MEL and RAM caused a rightward shift of Ang II in endothelium E + and endothelium E- aorta. According to the current study, the distribution of MEL receptors and the endothelium's condition are related to the vasomodulatory effect of MEL and ACE2 on Ang II attenuation. These physiological interactions can control vascular tone and increase Ang II reactivity denude endothelial layaer. [ABSTRACT FROM AUTHOR]

Copyright of Evaluation & Analysis of Drug-Use in Hospitals of China is the property of Evaluation & Analysis of Drug-Use in Hospitals of China Editorial Board and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Stroke is the leading cause of death and disability worldwide. Novel and effective therapies for ischemic stroke are urgently needed. Here, we report that melatonin receptor 1A (MT1) agonist ramelteon is a neuroprotective drug candidate as demonstrated by comprehensive experimental models of ischemic stroke, including a middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia in vivo, organotypic hippocampal slice cultures ex vivo, and cultured neurons in vitro; the neuroprotective effects of ramelteon are diminished in MT1‐knockout (KO) mice and MT1‐KO cultured neurons. For the first time, we report that the MT1 receptor is significantly depleted in the brain of MCAO mice, and ramelteon treatment significantly recovers the brain MT1 losses in MCAO mice, which is further explained by the Connectivity Map L1000 bioinformatic analysis that shows gene‐expression signatures of MCAO mice are negatively connected to melatonin receptor agonist like Ramelteon. We demonstrate that ramelteon improves the cerebral blood flow signals in ischemic stroke that is potentially mediated, at least, partly by mechanisms of activating endothelial nitric oxide synthase. Our results also show that the neuroprotection of ramelteon counteracts reactive oxygen species‐induced oxidative stress and activates the nuclear factor erythroid 2‐related factor 2/heme oxygenase‐1 pathway. Ramelteon inhibits the mitochondrial and autophagic death pathways in MCAO mice and cultured neurons, consistent with gene set enrichment analysis from a bioinformatics perspective angle. Our data suggest that Ramelteon is a potential neuroprotective drug candidate, and MT1 is the neuroprotective target for ischemic stroke, which provides new insights into stroke therapy. MT1‐KO mice and cultured neurons may provide animal and cellular models of accelerated ischemic damage and neuronal cell death. [ABSTRACT FROM AUTHOR]

Evidence suggests that the neuroprotective effects of melatonin involve both receptor‐dependent and ‐independent actions. However, little is known about the effects of melatonin receptor activation on the kainate (KA) neurotoxicity. This study examined the effects of repeated post‐KA treatment with ramelteon, a selective agonist of melatonin receptors, on neuronal loss, cognitive impairment, and depression‐like behaviors following KA‐induced seizures. The expression of melatonin receptors decreased in neurons, whereas it was induced in astrocytes 3 and 7 days after seizures elicited by KA (0.12 μg/μL) in the hippocampus of mice. Ramelteon (3 or 10 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) mitigated KA‐induced oxidative stress and impairment of glutathione homeostasis and promoted the nuclear translocation and DNA binding activity of Nrf2 in the hippocampus after KA treatment. Ramelteon and melatonin also attenuated microglial activation but did not significantly affect astroglial activation induced by KA, despite the astroglial induction of melatonin receptors after KA treatment. However, ramelteon attenuated KA‐induced proinflammatory phenotypic changes in astrocytes. Considering the reciprocal regulation of astroglial and microglial activation, these results suggest ramelteon inhibits microglial activation by regulating astrocyte phenotypic changes. These effects were accompanied by the attenuation of the nuclear translocation and DNA binding activity of nuclear factor κB (NFκB) induced by KA. Consequently, ramelteon attenuated the KA‐induced hippocampal neuronal loss, memory impairment, and depression‐like behaviors; the effects were comparable to those of melatonin. These results suggest that ramelteon‐mediated activation of melatonin receptors provides neuroprotection against KA‐induced neurotoxicity in the mouse hippocampus by activating Nrf2 signaling to attenuate oxidative stress and restore glutathione homeostasis and by inhibiting NFκB signaling to attenuate neuroinflammatory changes. [ABSTRACT FROM AUTHOR]

Background: The Society of Critical Care Medicine Clinical Practice Guidelines for Management of Pain, Agitation, Delirium, Immobility, and Sleep recommend protocolized non-pharmacologic sleep improvement. Pharmacologic interventions are frequently initiated to promote sleep but the evidence supporting these strategies remains controversial. Purpose: To systematically search and synthesize evidence evaluating pharmacologic sleep promotion modalities in critically ill adults. Methods: A rapid systematic review protocol was used to search Medline, Cochrane Library, and Embase for reports published through October 2022. We included randomized controlled trials (RCTs) and before-and-after cohort studies evaluating pharmacologic modalities intended to improve sleep in adult intensive care unit (ICU) patients. Sleep-related endpoints were the primary outcome of interest. Study and patient characteristics and relevant safety and non-sleep outcome data were also collected. The Cochrane Collaboration Risk of Bias or Risk of Bias in Non-Randomized Studies of Interventions were used to assess the risk of bias for all included studies. Results: Sixteen studies (75% RCTs) enrolling 2573 patients were included; 1207 patients were allocated to the pharmacologic sleep intervention. Most studies utilized dexmedetomidine (7/16; total n = 505 patients) or a melatonin agonist (6/16; total n = 592 patients). Only half of the studies incorporated a sleep promotion protocol as standard of care. Most (11/16, 68.8%) studies demonstrated a significant improvement in ≥1 sleep endpoint (n = 5 dexmedetomidine, n = 3 melatonin agonists, n = 2 propofol/benzodiazepines). Risk of bias was generally low for RCTs and moderate-severe for cohort studies. Conclusions: Dexmedetomidine and melatonin agonists are the most studied pharmacologic sleep promotion modalities, but current evidence does not support their routine administration in the ICU to improve sleep. Future RCTs evaluating pharmacologic modalities for ICU sleep should consider patients' baseline and ICU risks for disrupted sleep, incorporate a non-pharmacologic sleep improvement protocol, and evaluate the effect of these medication interventions on circadian rhythm, physiologic sleep, patient-perceived sleep quality, and delirium. [ABSTRACT FROM AUTHOR]

Background: Suvorexant and ramelteon have been presented as useful for preventing postoperative delirium. Previous studies reported on the comparison with benzodiazepine hypnotics which have been known for the risk for inducing delirium, but the comparison with patients not taking any hypnotics has not been reported yet. Therefore, we assessed the incidence rates for postoperative delirium comparing cancer patients who received preoperative combined administration with suvorexant and ramelteon and those not taking any hypnotics. Methods: Among 110 cancer patients who underwent surgeries at the Division of Hepato-Biliary-Pancreatic Surgery at the Shizuoka Cancer Center between April 1, 2017 and June 30, 2020, 50 patients who received combined administration with suvorexant and ramelteon from 7 days prior to their surgeries and 60 patients who did not take any hypnotics including suvorexant and ramelteon were classified. They were retrospectively observed during the 7 days from their surgeries onward to compare the cumulative incidence rates for postoperative delirium. Results: The cumulative incidence rate for postoperative delirium during the 7 days in the combined-administration group was 14.0% (7/50), while that for the no-hypnotic group was 36.7% (22/60), which proved that the incidence rate for the former was significantly low (OR: 0.28, 95%CI: 0.11–0.73, P = 0.009). Conclusions: The present study suggests that the preventive combined administration with suvorexant and ramelteon starting from the preoperative period for cancer patients can be effective in lowering the incidence rate for postoperative delirium. Trial registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]

Summary: Melatonin has gained growing interest as a treatment of insomnia, despite contradictory findings, and a low level of evidence. A systematic review and meta‐analysis was conducted following PRISMA criteria, to assess the efficacy of melatonin and ramelteon compared with placebo on sleep quantity and quality in insomnia disorder, while also considering factors that may impact their efficacy. This review included 22 studies, with 4875 participants, including 925 patients treated with melatonin, 1804 treated with ramelteon and 2297 receiving a placebo. Most studies evaluated the acute efficacy of prolonged release (PR) melatonin in insomnia disorder. Compared with placebo, PR melatonin appears efficacious with a small to medium effect size on subjective sleep onset latency (sSOL) (p = 0.031; weighted difference = −6.30 min), objective sleep onset latency (oSOL) (p < 0.001; weighted difference = −5.05 min), and objective sleep efficiency (oSE) (p = 0.043; weighted difference = 1.91%). For the subgroup mean age of patients ≥55, PR melatonin was efficacious on oSE with a large effect size (p < 0.001; weighted difference = 2.95%). Ramelteon was efficacious with a large effect size at 4 weeks on objective total sleep time (oTST) (p = 0.010; weighted difference = 17.9 min), subjective total sleep time (sTST) (p = 0.006; weighted difference = 11.7 min), sSOL (p = 0.009; weighted difference = −8.74 min), and oSOL (p = 0.017; weighted difference = −14 min). Regarding long‐term effects, ramelteon has a large effect size on oTST (p < 0.001; weighted difference = 2.02 min) and sTST (p < 0.001; weighted difference = 14.5 min). PR melatonin and ramelteon appear efficacious compared with placebo for insomnia symptoms with PR melatonin showing mostly small to medium effect sizes. PR melatonin for individuals with a mean age ≥ 55 and ramelteon show larger effect sizes. [ABSTRACT FROM AUTHOR]

Cytokine Storm Syndrome (CSs) is a potentially life threatening condition, characterized by robust elevated; of circulating pro-inflammatory cytokines; occurring after a hyperactive immune system. Is a well-known as a worldwide health problem, leading to multi-organ failure and death. Objectives: This study was carried out to investigate the protective role and probability of additive or synergistic anti-inflammatory activity; of ramelteon and in combination with dexamethasone on the lipopolysaccharide (LPS) induced "Cytokine Storm" on mice model and its potential regulatory mechanism(s). Methods: Sixty Swiss albino male mice of; (25 ± 5 grams; 8-12 weeks) had free access to food and water. After 2 weeks of adaptation, mice; randomly separated in five groups (n = 12): Group I, mice received (0.9% N/S i.p.); Group II, mice received (5 mg/kg i.p.) LPS only. Group III, mice received (2.5 mg/kg, i.p.) dexamethasone, Group IV, mice received (100 mg/kg i.p.) ramelteon, Group V, mice received half dose of dexamethasone+ ramelteon combination (1.25 mg/kg i.p +50 mg/kg i.p). For systematic inflammatory stimulation mimicking "cytokine storm" LPS; E. coli O55:B5 (5 mg/kg i.p.) was induced within one hr. After 48 h the effects of interventional agents and vehicle or LPS challenge; on lung, heart, liver, kidney histopathological changes, and levels of inflammatory cytokines: (IL-6, IL8, IL-1β, and TNF-α) in the serum were detected. Results: IL-1β, IL-6, IL8 and TNF-α elevated serum levels significantly reduced (P < 0.001) in all treatment group. Additionally, they ameliorated the histopathological changes induced by (LPS) and improving macroscopic scores (P < 0.001). Conclusion: In conclusion, ramelteon treatment had a diverse protective effects against "Cytokine Storm" with a mechanism based on attenuation serum levels of inflammatory cytokines (IL-1β, IL-6, IL-8 and TNF-α) and through reduction of histopathological damage during endotoxemia induced via LPS challenge on male mice model. RAM/DEX combination had superior advantage than an agent use alone probably via synergistic anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Although ramelteon has been examined as a relatively new therapeutic option for delirium prevention, current evidence to evaluate its efficacy is limited. We conducted an updated meta‐analysis and examine the reliability of existing evidence regarding the effect of ramelteon on delirium prevention in hospitalized patients. Seven major electronic databases were systematically searched to identify randomized controlled trials examining the efficacy of ramelteon in delirium prevention. Data were pooled using a frequentist‐restricted maximum‐likelihood random‐effects model. A trial sequential analysis was performed using relative risk reduction thresholds of 50%. The primary outcome was the incidence of delirium (reported as odds ratio with 95% confidence intervals). The secondary outcomes were the days of delirium, all‐cause mortality, and all‐cause discontinuation. Of 187 potentially eligible studies identified, 8 placebo‐controlled randomized controlled trials (n = 587) were included. This updated meta‐analysis showed that ramelteon was associated with lower odds of delirium occurrence than placebo (0.50; 0.29−0.86; I2 = 17.48%). In trial sequential analysis, the effect of ramelteon across the superiority boundary when using a relative risk reduction threshold ranging from 40% to 60%. In subgroup analyses, ramelteon compared with placebo was associated with lower odds of delirium occurrence in the elderly group (k = 5; 0.28; 0.09−0.85; I2 = 27.93%) and multiple dosage group (k = 5; 0.34; 0.14−0.82; I2 = 44.24%) but not in the non‐elderly and non‐multiple dosage groups. When considering surgical patients and medical patients separately, ramelteon showed a trend in the treatment of delirium prevention in both groups, while these findings were not statistically significant. No significant between‐group differences were found in the secondary outcomes. The current meta‐analysis provides updated and reliable evidence that ramelteon, in comparison with placebo, reduces the risk of delirium among hospitalized patients. [ABSTRACT FROM AUTHOR]

Copyright of Van Tip Dergisi is the property of Yuzuncu Yil University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Methotrexate (MTX) is an anticancer agent widely used in clinical practice for various oncological, rheumatological, autoimmune, and inflammatory diseases. However, the side effects of MTX limit its usage for treatment. In addition, diffuse alveolar damage, interstitial pneumonia, fibrosis, and pleural reactions may be encountered in MTX-induced pulmonary toxicity. Ramelteon (RML), a melatonin receptor agonist, has antioxidant, anti-inflammatory, and protective effects are shown by several studies. This study aimed to show the antioxidant, anti-inflammatory, and antiapoptotic effects of RML and its effect on the airway surface liquid volume homeostasis via aquaporins (AQP) in MTX-induced lung injury. Thirty-two female Wistar Albino rats were grouped into four groups as control, MTX (20 mg/kg, intraperitoneally, a single dose), MTX + RML, and RML (10 mg/kg, via oral gavage, for seven days) groups. Once the experiment ended, the rats' lung tissues were taken for biochemical, genetic, histopathological, and immunohistochemical examinations. MTX significantly increased oxidative stress index and total oxidative status, and decreased total antioxidant status levels by 202.0%, 141.4%, 20.2%, respectively, relative to the control (p ˂ 0.001 for all). AQP-1/5, which is an indicator of lung damage, was also found to decrease significantly (p ˂ 0.001). In addition, a significant increase was observed in interleukin-1β, interferon-beta, and caspase-8 expressions and histopathological changes as a result of immunohistochemical and histochemical examinations (p ˂ 0.001). RML treatment ameliorated all these changes and significantly regressed lung damage. Our results suggest that RML might be used as a lung-protective agent in various models of lung and tissue injury. [ABSTRACT FROM AUTHOR]

Copyright of Bezmialem Science is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Methotrexate is an important immunosuppressive and antineoplastic drug and is widely used for treatment. However, hepatotoxicity is one of the major adverse effects of methotrexate. In this study, it was aimed to investigate whether ramelteon has a possible protective effect on hepatotoxicity induced by methotrexate. Thirty-two Wistar albino rats were equally divided into four groups: control, methotrexate, methotrexate + ramelteon, and ramelteon. Following a single dose of 20 mg/kg, methotrexate (i.p.), either saline or ramelteon 10 mg/kg (orally) was administered for 7 days. After treatment, animals were sacrificed, and histopathological analyses were evaluated with Hematoxylin–eosin (H–E), immunohistological analyses were evaluated with Interleukın-1 Beta (IL-1β) and Caspase 3 (CAS-3), biochemical analyzes were evaluated with Total Oxidant Status (TOS), Total antioxidants status (TAS), Oxidative Stress Index (OSI), aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, at last genetical analyses were evaluated with Sirtuin-1 (SIRT-1) – P53 gene expressions. In the control and ramelteon groups, normal histological structures were observed, while histopathological findings were observed in the methotrexate group. Increasing levels of IL-1β staining, CAS-3 staining, p53 gene expression, TOS, OSI, AST and ALT were observed in methotrexate group while were observed decreasing levels of TAS and SIRT-1 gene expression (p < 0.05). However, ramelteon reduced the increased findings in methotrexate-induced hepatotoxicity (p < 0.05). The results of the present study showed that ramelteon protects against methotrexate induced hepatotoxicity in rats via SIRT-1 signaling by histological, immunohistological, biochemical and genetical analyses. [ABSTRACT FROM AUTHOR]

Objective(s): Methotrexate (MTX) is a widely used chemotherapeutic agent that, however, is known to have serious side effects such as neurotoxicity. In the present study, we aimed to evaluate the possible favorable effects of ramelteon (RMLT) on MTX-induced cerebral toxicity. Materials and Methods: Thirty-two male Wistar albino rats were divided into four groups: Control group, MTX group (20 mg/kg MTX, IP, single dose), MTX+RMLT group (20 mg/kg MTX, IP, single dose + 10 mg/kg RMLT, by gavage, 7 days), and RMLT group (10 mg/kg RMLT, by gavage, 7 days). Results: In the MTX group, increased levels of total oxidant status (TOS) and oxidative stress index (OSI) levels and decreased levels of total antioxidant status (TAS) level were observed. RMLT significantly reversed oxidative stress parameters. Real-time PCR analysis revealed that MTX increased the expressions of Beclin-1 and autophagy-related gene 12 (ATG12). These expressions were significantly decreased by RMLT. Vacuolar changes, apoptotic cells, and inflammatory cell infiltration induced by MTX were ameliorated by RMLT treatment. Increased tumor necrosis factor-α (TNF-α) and Caspase-3 activities induced by MTX were returned to their normal levels by RMLT. Conclusion: All our results demonstrate that RMLT alleviates the harmful effects of MTX on the cerebral cortex tissue. Therefore, RMLT may be considered for supportive therapy for preventing side effects of MTX in patients needing MTX therapy. [ABSTRACT FROM AUTHOR]

This study aimed to determine the underlying mechanism of ramelteon on the competence of oocyte and subsequent embryo development in pigs during in vitro maturation (IVM). Our results showed that the cumulus expansion index was significantly lower in the control group compared to the ramelteon groups (p < 0.05). Moreover, supplementation of 10−11 and 10−9 M ramelteon significantly increased the cumulus expansion and development-related genes expression, and reduced apoptosis in cumulus cells (p < 0.05). In oocytes, the nuclear maturation rate was significantly improved in 10−11, 10−9, and 10−7 M ramelteon groups compared to the control (p < 0.05). Additionally, the level of intracellular GSH was significantly increased and ROS was significantly decreased in ramelteon-supplemented groups, and the gene expression of oocyte development and apoptosis were significantly up- and down-regulated by 10−11 and 10−9 M ramelteon (p < 0.05), respectively. The immunofluorescence results showed that the protein levels of GDF9, BMP15, SOD1, CDK1, and PGC1α were significantly increased by 10−11 M ramelteon compared to the control (p < 0.05). Although there was no significant difference in cleavage rate, the blastocyst formation rate, total cell numbers, and hatching/-ed rate were significantly improved in 10−11 M ramelteon group compared to the control (p < 0.05). Furthermore, embryo development, hatching, and mitochondrial biogenesis-related genes were dramatically up-regulated by 10−11 M ramelteon (p < 0.05). In addition, the activities of lipogenesis and lipolysis in oocytes were dramatically increased by 10−11 M ramelteon compared to the control (p < 0.05). In conclusion, supplementation of 10−11 M ramelteon during IVM improved the oocyte maturation and subsequent embryo development by reducing oxidative stress and maintenance of lipid homeostasis. [ABSTRACT FROM AUTHOR]

Copyright of General Medicine & Health Sciences / Medycyna Ogólna i Nauki o Zdrowiu is the property of Witold Chodzki Institute of Rural Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Melatonin is a human neurotransmitter and plant signalling metabolite that perceives and directs plant metabolism. The mechanisms of melatonin action in plants remain undefined. We hypothesized that roots have a melatonin-specific receptor and/or transporter that can respond to melatonin-mediating pharmaceuticals. To test this hypothesis Arabidopsis seedlings were grown with melatonin pharmaceutical receptor agonists: ramelteon and tasimelteon, and/or antagonists: luzindole and 4-P-PDOT. Ramelteon was found both to mimic and competitively inhibit melatonin metabolism in plants. Due to the higher selectivity of ramelteon for the MT1 receptor type in humans, a sequence homology search for MT1 in Arabidopsis identified the rhomboid-like protein 7 (RBL7). In physiological studies, Arabidopsis rbl7 mutants were less responsive to ramelteon and melatonin. Quantum dot visualizations of the effects of ramelteon on melatonin binding to root cell membranes revealed a potential mechanism. We propose that RBL7 is a melatonin-interacting protein that directs root architecture and growth in a mechanism that is responsive to environmental factors. [ABSTRACT FROM AUTHOR]

Aims: Several factors related to vancomycin‐induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high‐risk combinations that influence VIN. Methods: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine ≥0.5 mg/dL or 1.5‐fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. Results: Of the 7306 patients that were enrolled, VIN occurred in 14.2% of them (1035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio 0.701, 95% confidence interval 0.512‐0.959), ward pharmacy service (0.741, 0.638‐0.861), duration of VCM < 7 days (0.748, 0.623‐0.899) and trough concentrations 10‐15 mg/L (0.668, 0.556‐0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin‐tazobactam use (2.056, 1.754‐2.409) and piperacillin use (2.868, 1.298‐6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations ≥20 mg/L and concomitant piperacillin‐tazobactam use was associated with the highest risk. Conclusions: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin‐tazobactam but also piperacillin may increase the risk. [ABSTRACT FROM AUTHOR]

Background: Circadian rhythms is a natural process that regulates the sleep wake cycle which is associated with several physiological, biochemical, endocrine, behavioural processes in humans and entrainment to light-dark cycle. The activity of Ramelteon is believed to contribute to its sleep-promoting properties and thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. A tablet can be given before 2 hr of bed time, so the Ramelteon drug shows its effect throughout the night by releasing the active content with lag time followed by sustained action to promote the sleep. Materials and Methods: Chronotherapeutic drug delivery system were prepared by compression coating technology using pH independent, hydrophilic and hydrophobic polymers. Results: Drug excipient compatibility indicated that the Ramelteon Active pharmaceutical ingredient (API) is compatibility with the excipients proposed. The X-ray Diffraction (XRD) studies indicated that the crystalline form of the Ramelteon API existed in the finished formulation. Conclusion: The core tablets containing Eudragit RSPO 10mg/tablet and ratio of Ethyl cellulose: Hydroxy propyl methyl cellulose (HPMC) of 70:30 in the outer coating material yielded a desired lag time of 2 hr and drug release for a period of 4 hr to achieve a chronotherapeutic drug delivery system. Ramelteon is an excellent candidate in designing chronotherapeutic drug delivery systems and further in vivo studies can be explored in the treatment of circadian rhythm with sleep wake cycle disorders. [ABSTRACT FROM AUTHOR]

Objective: Metabolic side effects are a limiting factor in the use of antipsychotics, which remain the cornerstone of long‐term management of patients with severe mental illness. There is contrasting evidence on a possible role of melatonin and melatonin‐agonists in attenuating antipsychotic‐induced metabolic abnormalities. Design: We conducted a systematic review (PubMed, PsycInfo, Cochrane databases, up to August 2020) and a random‐effect meta‐analysis of double‐blind, randomized placebo‐controlled trials (RCTs) involving melatonin and melatonin‐agonists in the treatment of antipsychotic‐induced metabolic changes. The primary outcome was the standardized mean difference (SMD) of composite metabolic outcomes built with metabolic syndrome components. Secondary outcomes were individual metabolic syndrome components, and other anthropometric, glucose metabolism, lipid profile, and psychopathology measures. Results: Out of the initial 41 studies, six documented five separate RCTs randomizing 248 patients (126 to melatonin/ramelteon, 122 to placebo) affected by schizophrenia‐spectrum disorders and bipolar disorder. Melatonin/ramelteon outperformed placebo on the primary outcome (SMD −0.28, 95% CI = −0.39 ÷ −0.168), as well as on all individual components of metabolic syndrome (systolic blood pressure MD −3.266, 95% CI = −6.020 ÷ −0.511; fasting glucose MD −3.766, 95% CI = −5.938 ÷ −1.593; triglycerides MD −9.800, 95% CI = −19.431 ÷ −0.169; HDL MD 2.995, 95% CI = 0.567 ÷ 5.423), except waist circumference. Conclusions: Melatonin/ramelteon augmentation may be beneficial for non‐anthropometric metabolic syndrome components in patients treated with antipsychotics. [ABSTRACT FROM AUTHOR]

Aim: A melatonin receptor agonist ramelteon is a drug that is also used in urinary tract infections. Melatonin is known to have an effect on smooth muscle contraction. In this study, we aimed to question whether ramelteon exerts a melatonin-like effect on bladder contractions. Material and Methods: Wistar-albino (n = 8) intact female rats were used in the study. After decapitation, 1.5x5 mm bladder strips were examined in an isolated organ bath in which there was Krebs-Henseleit solution. After the regulation period, ramelteon was applied non-cumulatively in two separate doses of 0.2µM, 1µM. The area under the curve (AUC) and peak to peak (p-p) values before and after the application were normalized as % change. Results: Exposure of bladder strips to ramelteon significantly increased contractions. Ramelteon caused a statistically significant increase in p-p, AUC values of spontaneous bladder contractions at a dose of 0.2 and 1µM (p < 0.05). Conclusion: Ramelteon has an activator effect on spontaneous bladder contractions unlike melatonin. The physiopathological mechanisms under activator activity need to be investigated with further studies. This effect should be taken into account in clinical use. [ABSTRACT FROM AUTHOR]

Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether suvorexant with or without ramelteon prevents delirium in elderly hospitalized patients, we conducted a systematic review and meta‐analysis to evaluate, searching the PubMed, Cochrane Library, Web of Science, EMBASE, and EBSCOhost databases for all randomized controlled trials (RCTs), case–control studies, and cohort studies that investigated the effects of suvorexant with or without ramelteon on delirium in adult hospitalized patients. The primary outcome was the incidence of delirium. Two randomized controlled trials, 7 cohort studies and 2 case–control studies involving 2594 patients were included in this meta‐analysis. The results showed that both suvorexant alone (odds ratio (OR) = 0.30, 95% confidence interval (CI): 0.14–0.65, P = 0.002) and suvorexant with ramelteon (OR = 0.39, 95% CI 0.23–0.65, P = 0.0003) reduced the incidence of delirium in adult hospitalized patients. Six studies involved the use of benzodiazepines; subgroup analysis performed separately in the suvorexant alone and suvorexant with ramelteon groups indicated that when benzodiazepine was administered, suvorexant with ramelteon was effective at reducing the incidence of delirium (OR = 0.53, 95% CI 0.37–0.74, P = 0.0002), but no significant difference was observed for suvorexant alone (OR = 0.40, 95% CI 0.11–1.53, P = 0.18). The current literature thus supports the effectiveness of suvorexant with or without ramelteon for delirium prevention, although suvorexant alone failed to significantly reduce the incidence of delirium when benzodiazepine was administered. The present study was limited by the significant heterogeneity among the included studies, and caution should be exercised when interpreting the results. This study was registered in the PROSPERO database (CRD4202017964). [ABSTRACT FROM AUTHOR]

As the COVID‐19 pandemic grows, several therapeutic candidates are being tested or undergoing clinical trials. Although prophylactic vaccination against SARS‐CoV‐2 infection has been shown to be effective, no definitive treatment exists to date in the event of infection. The rapid spread of infection by SARS‐CoV‐2 and its variants fully warrants the continued evaluation of drug treatments for COVID‐19, especially in the context of repurposing of already available and safe drugs. Here, we explored the therapeutic potential of melatonin and melatonergic compounds in attenuating COVID‐19 pathogenesis in mice expressing human ACE2 receptor (K18‐hACE2), strongly susceptible to SARS‐CoV‐2 infection. Daily administration of melatonin, agomelatine, or ramelteon delays the occurrence of severe clinical outcome with improvement of survival, especially with high melatonin dose. Although no changes in most lung inflammatory cytokines are observed, treatment with melatonergic compounds limits the exacerbated local lung production of type I and type III interferons, which is likely associated with the observed improved symptoms in treated mice. The promising results from this preclinical study should encourage studies examining the benefits of repurposing melatonergic drugs to treat COVID‐19 and related diseases in humans. [ABSTRACT FROM AUTHOR]

Acute ischemic stroke is a challenging disease that threatens the life of older people. Dysfunction of brain endothelial cells is reported to be involved in the pathogenesis of acute ischemic stroke. Ramelteon is a novel agonist of melatonin receptor developed for the treatment of insomnia. Recently, the promising protective effect of Ramelteon on brain injury has been widely reported. The present study aims to investigate the protective effect of Ramelteon against free fatty acid (FFA)–induced damages in brain vascular endothelial cells and the underlying mechanism. Firstly, we discovered that Ramelteon administration remarkably reversed the decreased cell viability, increased LDH release, activated oxidative stress, and excessive released inflammatory factors caused by FFAs. Secondly, Ramelteon extensively suppressed the attachment of U937 monocytes to bEnd.3 brain endothelial cells induced by FFAs. In addition, the elevated expression of E-selectin and the reduced expression of KLF2 induced by FFAs were pronouncedly alleviated by Ramelteon. Lastly, silencing of KLF2 abolished the protective effects of Ramelteon against FFA-induced expression of E-selectin and the attachment of U937 monocytes to bEnd.3 brain endothelial cells. In conclusion, Ramelteon mitigated FFA-induced attachment of monocytes to brain vascular endothelial cells by increasing the expression of KLF2 and reducing the expression of E-selectin. [ABSTRACT FROM AUTHOR]

Background: An impaired sleep-wake cycle may be one factor that affects the development of delirium in critically ill patients. Several small studies suggest that exogenous melatonin or ramelteon may decrease the incidence and/or duration of delirium. Objective: To compare the effect of prophylactic administration of melatonin, ramelteon, or no melatonin receptor agonist on the development of delirium in the intensive care unit (ICU). Methods: This was a single-center, retrospective, observational cohort study of nondelirious patients in the ICU who received melatonin, ramelteon, or no melatonin receptor agonist. The primary end point was the incidence of delirium. Secondary end points included assessments of daily level of sedation and daily utilization of antipsychotic, sedative, and opioid agents. Results: No difference was observed in the incidence of delirium among the melatonin, ramelteon, and placebo cohorts (18.7% vs 14.3% vs 13.8%; P = 0.77). A difference was observed in the rate of agitation and sedation among the 3 groups, with the greatest observed in the melatonin cohort. Additionally, there was a difference in the use of propofol, dexmedetomidine, and opioids. Overall, there was no difference in clinical outcomes, including duration of mechanical ventilation and ICU or hospital length of stay. Conclusion and Relevance: Therapy with melatonin, ramelteon, and no melatonin receptor agonist resulted in similar rates of delirium in a mixed ICU population. Despite significant differences in agitation, sedation, and medication utilization, there was no differences in the clinical outcomes evaluated. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) is important for protecting the brain tissue by selectively exchanging substances between the blood and brain. The integrity of the BBB can be damaged by multiple factors, including oxidative stress and inflammation. Ramelteon is an oral hypnotic drug, and in the present study, we investigated its protective effect on BBB damage, as well as the underlying mechanism. LPS was used to induce BBB damage on mice and stimulate injury on endothelial cells. Evans blue staining assay was used to measure the brain permeability. The expressions of ZO-1 and Occludin were evaluated using immunostaining and Western blot in the brain tissue and endothelial cells, respectively. qRT-PCR and ELISA were used to detect the production of IL-1β and MCP-1 in the brain vessels. TBA assay was utilized to examine the concentration of MDA in the brain tissue and endothelial cells. The expression of Nrf2 in the nucleus and NQO1 were determined using Western blot assay. The endothelial permeability of the monolayer was examined using the FITC-dextran permeation assay. Firstly, the increased brain permeability and downregulated expression of tight junction proteins in the brain tissue induced by LPS were significantly reversed by treatment with Ramelteon, accompanied by the decrease in the production of IL-1β and MCP-1 in the vessels in mice. Also, the Nrf2 signaling was activated and oxidative stress in the brain vessels was alleviated by treatment with Ramelteon. Secondly, LPS-induced increase in endothelial monolayer permeability and decrease in tight junction protein expression in bEnd.3 brain endothelial cells were significantly reversed by Ramelteon, accompanied by activated Nrf2 signaling and alleviated oxidative stress. Lastly, the protective effects of Ramelteon against LPS-induced reduction of ZO-1 and Occludin, and the increase in endothelial monolayer permeability were dramatically abolished by silencing Nrf2. Ramelteon might ameliorate LPS-induced hyperpermeability of the BBB by activating the Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Anesthetic-induced cognitive impairment has been observed clinically. The mechanism underlying anesthetic-induced cognitive impairment is closely associated with neuronal apoptosis and neuroinflammation. Ramelteon is a potent and highly selective melatonin receptor agonist that has been used for the treatment of insomnia and has been reported to have an anti-inflammatory effect. In this study, we aimed to investigate the protective effects of Ramelteon against the cytotoxicity induced by isoflurane in brain microvascular endothelial cells. Our results show that Ramelteon ameliorated oxidative stress by suppressing the generation of mitochondrial reactive oxygen species (ROS) in human brain microvascular endothelial cells (HBMVECs). In addition, Ramelteon displayed a robust anti-inflammatory capacity against isoflurane-induced insults and inflammation by reducing the generation of interleukin-1β (IL-1β), transforming growth factor-β (TGF-β), monocyte chemotactic protein 1 (MCP-1), stromal cell-derived factor-1 (SDF-1), matrix metalloproteinase-2 (MMP-2), and MMP-9. Furthermore, Ramelteon reduced the expression of cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Importantly, Ramelteon downregulated the activation of the p38MAPK/NF-κB signaling pathway, which is the key transcriptional regulator in the inflammation process. Our findings in the present study provide new evidence for the use of Ramelteon in the prevention of isoflurane-induced insults in brain endothelial cells. [ABSTRACT FROM AUTHOR]

Extensive research has gone into proposing a promising link between melatonin administration and attenuation of epileptic activity, the majority of which suggest its propensity as an antiseizure with antioxidant and neuroprotective properties. In the past few years, a number of studies highlighting the association of the melatonergic ligands with epilepsy have also emerged. In this context, our review is based on discussing the recent studies and various mechanisms of action that the said category of drugs exhibit in the context of being therapeutically viable antiseizure drugs. Our search revealed several articles on the four major drugs i.e. melatonin, agomelatine, ramelteon and piromelatine along with other melatonergic agonists like tasimelteon and TIK-301. Our review is suggestive of antiseizure effects of both melatonin and its analogues; however, extensive research work is still required to study their implications in the treatment of persons with epilepsy. Further evaluation of melatonergic signaling pathways and mechanisms may prove to be helpful in the near future and might prove to be a significant advance in the field of epileptology. [ABSTRACT FROM AUTHOR]

Introduction: Non‐24‐hour sleep‐wake disorder (N24SWD) is often observed in the visually impaired and those who isolate indoors. Melatonin receptor agonists may be used for treatment, but there is currently no evidence that they are effective in patients without visual impairment. Case: We report a case of a 23‐year‐old woman who withdrew from her social life owing to autism spectrum disorder and experienced an unusual sleep rhythm. She presented with N24SWD. The N24SWD cycle averaged 25.6 days but was extended to 42 days using ramelteon. However, this was not enough. We prescribed the addition of suvorexant and the sleep cycle returned to normal. Conclusion: N24SWD is a disease that seriously impairs social life and productivity. We propose a possible treatment strategy for N24SWD using ramelteon and suvorexant. [ABSTRACT FROM AUTHOR]

In intensive care unit (ICU) patients, delirium contributes to prolonged hospitalization, long-term cognitive impairment and increased mortality. Sleep disturbance, a risk factor for delirium, has been attributed to impaired melatonin secretion in critically ill patients. Ramelteon, a synthetic melatonin receptor agonist, is indicated for insomnia; there is limited, but growing evidence, to support its use for the prevention of delirium. The primary objective of this study is to describe the use of ramelteon and the incidence of delirium, assessed by Confusion Assessment Method for the ICU (CAM-ICU) scores, in adult surgical ICU patients from May 22, 2016 to June 30, 2018. The primary endpoint is the number of delirium free days in the week prior to and post first ramelteon administration. A total of 231 patients were included in the study with 201 (87%) positive for delirium at least once during the study timeframe. The median number of CAM-ICU negative days in the week pre-ramelteon administration was 4 days (IQR 2-7 days) compared to 6 days (IQR 3-7 days) in the week post-first ramelteon administration (P <.05). The time to CAM-ICU positive increased slightly to 3 days (IQR 1-7 days) following ramelteon initiation compared to 2 days (IQR 1-5 days) from initial ICU admission. Additionally, the median number of antipsychotic doses per patient decreased from 4 doses (IQR 1.25-14 doses) prior to ramelteon to 2 doses (IQR 1-4 doses) after ramelteon. Ramelteon administration was associated with a greater number of CAM-ICU negative days in surgical ICU patients. These findings describe a potential role for ramelteon in mitigating delirium in this patient population. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine the effect of an intervention consisting of bright light exposure, sleep schedule shifts, and ramelteon on sleep disturbances after a transition of 12 time zones. Two groups, which flew from Tokyo to Rio, participated in this study. The experimental group received the treatment, whereas the control group did not receive any treatment. The experimental group members were exposed to bright light at night and their sleep-wake schedules were gradually delayed for 4 days before their flight. They also took 8mgof ramelteon once a day for 5 days fromthe day of their first flight. Both groups departed Tokyo at 14:05, transiting through Frankfurt and arriving in Rio at 05:05. In Rio, it was recommended that they go to bed earlier than usual if they experienced sleepiness. Nocturnal sleep variablesmeasured bywristwatch actigraphy and subjective morning tirednesswere compared between groups. Statistical analysis revealed shorter sleep onset latencies (SOLs) in the experimental group (p<0.01). The SOLs inRio were 7.762.5minutes for the experimental group and 16.363.7minutes for the control group (d50.89, effect size: large). Sleep efficiency for the first 3 nights in Rio was 88.5 ± 1.2% for the experimental group and 82.9 ± 3.0% for the control group (p<0.01, d51.09, effect size: large). These results suggest that the intervention reduced sleep disturbances in Rio. Our intervention may increase the options for conditioning methods for athletic events requiring time zone transitions. [ABSTRACT FROM AUTHOR]

It remains unclear whether melatonin and its analogues prevent postoperative delirium (POD). Therefore, we conducted a systematic review and meta‐analysis to evaluate the effect of melatonin and its analogues on POD prevention. PubMed, Cochrane Library, Web of Science, Embase and CINAHL databases were searched. Primary outcome was the incidence of POD. Six randomized controlled trials, 2 cohort studies and 1 case‐control study were included in this meta‐analysis. Results showed that melatonin and its analogue ramelteon decreased the incidence of POD in the entire adult surgical population (odds ratio [OR] = 0.45, 95% confidence interval [CI] 0.24‐0.84, P =.01). When administered at a higher dose (5 mg), melatonin was effective in reducing the POD incidence (OR = 0.32, 95% CI 0.20‐0.52, P <.00001). Melatonin administered less than 5 elimination half‐lives before the surgery significantly reduced the POD incidence (OR = 0.31, 95% CI 0.19‐0.49, P <.00001). Current literature supports the effectiveness of melatonin and its analogue ramelteon in POD prevention. However, the present study was limited by the significant heterogeneity of the included studies. More studies are needed to ascertain the preventive effect of melatonin and its analogues on the incidence of delirium after cardiac and noncardiac surgeries. [ABSTRACT FROM AUTHOR]

Background: It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin has been reported to be effective in animal models of acute lung injury. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. However, it is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). Therefore, in this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection.Methods: VILI was induced by high tidal volume ventilation in a rat model. The rats were randomly allotted into the following groups: control, control+melatonin, control+ramelteon, control+luzindole, VILI, VILI+luzindole, VILI + melatonin, VILI + melatonin + luzindole (melatonin receptor antagonist), VILI + ramelteon, and VILI + ramelteon + luzindole (n = 6 per group). The role of interleukin-10 (IL-10) in the melatonin- or ramelteon-mediated protection against VILI was also investigated.Results: Ramelteon treatment markedly reduced lung edema, serum malondialdehyde levels, the concentration of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), NF-κB activation, iNOS levels, and apoptosis in the lung tissue. Additionally, ramelteon treatment significantly increased heat shock protein 70 expression in the lung tissue and IL-10 levels in BALF. The protective effect of ramelteon was mitigated by the administration of luzindole or an anti-IL-10 antibody.Conclusions: Our results suggest that a melatonin receptor agonist has a protective effect against VILI, and its protective mechanism is based on the upregulation of IL-10 production. [ABSTRACT FROM AUTHOR]

In intensive care unit (ICU) patients, delirium contributes to prolonged hospitalization, long-term cognitive impairment and increased mortality. Sleep disturbance, a risk factor for delirium, has been attributed to impaired melatonin secretion in critically ill patients. Ramelteon, a synthetic melatonin receptor agonist, is indicated for insomnia; there is limited, but growing evidence, to support its use for the prevention of delirium. The primary objective of this study is to describe the use of ramelteon and the incidence of delirium, assessed by Confusion Assessment Method for the ICU (CAM-ICU) scores, in adult surgical ICU patients from May 22, 2016 to June 30, 2018. The primary endpoint is the number of delirium free days in the week prior to and post first ramelteon administration. A total of 231 patients were included in the study with 201 (87%) positive for delirium at least once during the study timeframe. The median number of CAM-ICU negative days in the week pre-ramelteon administration was 4 days (IQR 2-7 days) compared to 6 days (IQR 3-7 days) in the week post-first ramelteon administration (P< .05). The time to CAM-ICU positive increased slightly to 3 days (IQR 1-7 days) following ramelteon initiation compared to 2 days (IQR 1-5 days) from initial ICU admission. Additionally, the median number of antipsychotic doses per patient decreased from 4 doses (IQR 1.25-14 doses) prior to ramelteon to 2 doses (IQR 1-4 doses) after ramelteon. Ramelteon administration was associated with a greater number of CAM-ICU negative days in surgical ICU patients. These findings describe a potential role for ramelteon in mitigating delirium in this patient population. [ABSTRACT FROM AUTHOR]

Ramelteon is the first medicine in human history that treat insomnia as a melatonin receptor agonist. Herein, we report an efficient three‐step synthetic route to access it from commercially available 2,3‐dihydrobenzofuran‐4‐amine, which represents as the shortest racemic synthesis to date with a 26 % overall yield. Key to the success is the application of the intermolecular Catellani‐type alkylation and intramolecular redox‐relay Heck cyclization cascade for preparation of the key indane‐containing aldehyde. The unique primary amide‐involved reductive amination of aldehyde is another feature of this route. New process of ramelteon can be developed based on this chemistry. [ABSTRACT FROM AUTHOR]

The purpose is to evaluate the effect and safety of ramelteon 8 mg/day for 8 weeks in the treatment of insomnia in patients with concurrent depression in an exploratory manner. This phase 4, open-label, exploratory study included outpatients aged 20 to < 65 years with sleep-onset insomnia and major depressive disorder taking stable antidepressant medication. Following a 1-week run-in, 26 eligible patients received ramelteon 8 mg/day plus their usual antidepressants for 8 weeks. Outcomes included sleep parameters measured by actigraphy and sleep diary, 3-Dimensional Sleep Scale (3DSS), 17-item Hamilton Rating Scale for Depression (HAM-D17), Patient Global Impression (PGI), adverse events, and body weight. Actigraphy- and diary-measured sleep latency improved at the end of ramelteon treatment (mean decrease − 6.8 and − 11.5 min, respectively), but neither change reached statistical significance in this exploratory study. Other subjective measures indicated improved sleep, including diary-measured total sleep time (mean change + 41.2 min; p =.0220) and number of nocturnal awakenings (−.4; p =.0420), and 3DSS total scores for sleep quality and quantity (p <.01). Most patients (88.5%) reported improvement in PGI. HAM-D17 total scores improved at end of treatment (mean change − 4.0; p <.0001). One patient discontinued ramelteon due to moderate somnolence. Ramelteon coadministered with antidepressants was well tolerated. Results from this exploratory study suggest that ramelteon may be effective and well tolerated in the treatment of sleep-onset insomnia in patients with concurrent depression. [ABSTRACT FROM AUTHOR]

We conducted a multicenter, open-label, observational study to evaluate the effectiveness and safety of ramelteon in patients with insomnia, and patient characteristics affecting treatment response in routine clinical practice. Eligible patients were aged ≥ 20 years, had a diagnosis of insomnia with difficulty falling asleep, and were scheduled to receive ramelteon 8 mg/day for 12 weeks. The primary objective was to evaluate the relationship between changes in insomnia severity [measured by the Insomnia Severity Index (ISI)] and patient characteristics. Changes in the physical (PCS-8) and mental (MCS-8) components of the Short Form-8 (SF-8), and safety were also investigated. 1527 patients received therapy; 40.5% were aged ≥ 65 years and 29.7, 56.9, and 13.4% had mild, moderate, or severe insomnia, respectively. At week 12, significant improvements in ISI score [mean change (standard deviation) from baseline, − 5.0 points (6.3); p <.0001], PCS-8 score [+ 2.40 points (8.71); p <.0001], and MCS-8 score [+ 3.68 points (9.47); p <.0001] were observed. Factors affecting ISI response or remission (based on adjusted odds ratios) included age ≥ 75 years, shorter disease duration, no alcohol intake, being employed full time, not taking concomitant medication for insomnia, and taking ramelteon more than 1 h before bedtime. In total, 5.9% of patients reported adverse drug reactions. In routine clinical practice, 12 weeks' therapy with ramelteon was effective at improving insomnia severity, with no new safety concerns identified. Several patient characteristics were found to influence response to therapy. Clinical trial identifier: UMIN000013271 [ABSTRACT FROM AUTHOR]

Omega-3 polyunsaturated fatty acids (n-3 or omega-3 PUFAs) and melatonin receptor agonist ramelteon (RMT) both display antidepressant effects, while their cellular effects on anti-oxidative and neuroprotective mechanisms might be different. In this study, we aimed to decipher the individual and synergistic actions of n-3 PUFAs and RMT, as compared with the conventional antidepressant fluoxetine (FLX), in a cellular model of oxidative stress, which might play an important role in the pathophysiology of depression and associated disorders. We investigated the rescue and prevention effects of FLX, RMT, and n-3 PUFAs, e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by using cell viability in SH-SY5Y cells under oxidative stress along with measurements of key cellular markers of oxidative stress, inflammatory, and neuroprotection. The results revealed that the RMT and EPA combination significantly increased the cell viability in a dose-dependent manner. RMT showed preventive effects, FLX and DHA possessed rescue effects, while EPA showed both rescue and preventive effects. We observed the dose-dependent activation and translocation of nuclear factor-κB to the nucleus augmented by the expressions of peroxisome proliferator activator receptor-gamma, tyrosine hydroxylase, c-Fos expression, and reactive oxygen species, implying that RMT and EPA combination reversed oxidative and neuroinflammatory pathophysiology and protected the neuronal cells from further damage. The results demonstrated that RMT and EPA synergistically provide effective neuroprotective, anti-oxidative/inflammatory effect against oxidative stress. Our study provides pre-clinical evidence to conduct future clinical trials of using n-3 PUFAs/RMT combination in depressive disorders. [ABSTRACT FROM AUTHOR]

The objective of the study was to investigate the efficacy of ramelteon for insomnia, particularly with circadian disturbance, focusing on the relevance of dose and timing of administration. We reviewed the chart data of 145 continuous patients who received ramelteon for insomnia for the first time at the sleep clinic of the Department of Psychiatry, Fujita Health University Hospital (Aichi, Japan) between October 2010 and May 2014. Treatment efficacy was assessed using the Clinical Global Impression of Improvement (CGI-I) scale and this relationship with the dose and timing of administration was further analyzed. Symptoms in 56.6% of patients were improved (CGI-I ≦ 3). In a subgroup of 114 patients, especially aiming for phase advance, the ratio of improvement was 64.0%. The ratio of patients reporting symptom improvement tended to be great in the low-dose (1 or 2 mg) group and the low-dose + early administration (> 5 h before habitual bedtime) group, as compared with the remaining group; however, this difference was not statistically significant. Significantly fewer cases in the low-dose group reported carry-over effects. In our specialized sleep clinic, there were many refractory cases of insomnia; however, ramelteon was effective in about half of such patients. Particularly, ramelteon tended to be more effective for patients with insomnia and circadian disturbances, although differences among groups were not statistically significant. The effectiveness of the low-dose administration or the combination of low-dose and early-administration was equal or slightly better and acceptability tended to be better than other modes of administration. [ABSTRACT FROM AUTHOR]

Background: Postoperative delirium is common after extensive surgery, and is known to be associated with sleeping medications. In this study, we aimed to investigate the relationships between sleeping medications and postoperative delirium after pharyngolaryngectomy with esophagectomy. Methods: We performed a retrospective analysis of 65 patients who underwent pharyngolaryngectomy with esophagectomy at Shizuoka Cancer Center Hospital between January 2012 and March 2016. All data were assessed by two psychiatrists, and univariate and multivariate analyses were performed. Results: Postoperative delirium developed in 9 (13.8%) patients, with most cases (77.8%) occurring between postoperative day (POD) 1 and POD 3. Of the 24 patients taking a minor tranquilizer after surgery, 8 (33.3%) became delirious, but, of the remaining 41 patients taking ramelteon with or without suvorexant, only one (2.4%) became delirious after surgery. Moreover, of the 16 patients taking both ramelteon and suvorexant, no postoperative delirium was observed. Ramelteon with or without suvorexant was significantly associated with a decreased rate of postoperative delirium compared with minor tranquilizer use ( p = 0.001). Multivariate analysis confirmed that the use of ramelteon with or without suvorexant was the only significant preventive factor of postoperative delirium (odds ratio 0.060, p = 0.013). Conclusion: The use of ramelteon with or without suvorexant was the only significant preventive factor of postoperative delirium after pharyngolaryngectomy with esophagectomy. However, using minor tranquilizers was associated with postoperative delirium. We recommend ramelteon with or without suvorexant for preventing postoperative delirium after pharyngolaryngectomy with esophagectomy. [ABSTRACT FROM AUTHOR]

The incidence of endometrial cancer is increasing, making it the fifth most common cancer worldwide. To date, however, there is no standard therapy for patients with recurrent endometrial cancer. Melatonin, a hormone secreted by the pineal gland, has been shown to have anti-tumor effects in various tumor types. Although melatonin is available as a supplement, it has not been approved for cancer treatment. Ramelteon, a selective melatonin receptor type 1 and 2 (MT1/MT2) receptor agonist, has been approved to treat sleep disorders, suggesting that ramelteon may be effective in the treatment of endometrial cancer. To determine whether this agent may be effective in the treatment of endometrial cancer, this study investigated the ability of ramelteon to suppress the proliferation and invasiveness of HHUA cells, an estrogen receptor-positive endometrial cancer cell line. Ramelteon at 10 M maximally suppressed the proliferation of HHUA cells, reducing the percentage of Ki-67 positive proliferating cells. This effect was completely blocked by luzindole, a MT1/MT2 receptor antagonist. Furthermore, ramelteon inhibited HHUA cell invasion and reduced the expression of the MMP-2 and MMP-9 genes. These results suggested that ramelteon may be a candidate for the treatment of recurrent endometrial cancer, with activity similar to that of melatonin. [ABSTRACT FROM AUTHOR]

Delirium, an acute state of mental confusion, can lead to many adverse sequelae in intensive care unit (ICU) patients. Although the etiology of ICU delirium is often multifactorial, and at times not fully understood, sleep deprivation is considered to be a major contributing factor to its development. It has been postulated that administration of exogenous melatonin and melatonin receptor agonists such as ramelteon may prevent delirium by promoting nocturnal sleep in ICU patients. The purpose of this review is to summarize the pharmacology of melatonin and melatonin receptor agonists and investigate their potential roles in sleep promotion and delirium prevention in ICU patients. Although few studies evaluating the impact of melatonergic agents on sleep and delirium in the ICU have been completed, some data suggest their potential positive effects on sleep and delirium. However, large-scale randomized controlled trials are warranted to determine the optimal role of melatonergic agents in the prevention of ICU delirium. [ABSTRACT FROM AUTHOR]

Rationale: Hypnotics are widely used to treat insomnia but adverse effects of different hypnotics, especially benzodiazepine receptor agonists, are getting more attention lately. The effects of novel hypnotics have not been fully examined. Objective: This study aims to assess the effects of two hypnotics, ramelteon and triazolam, on driving performance, cognitive function, and equilibrium function. Methods: In this double-blinded, three-way crossover trial, 17 healthy males received acute doses of 8 mg ramelteon, 0.125 mg triazolam, and placebo. The subjects were administered three driving tasks-road-tracking, car-following, and harsh-braking-using a driving simulator and three cognitive tasks-Continuous Performance Test, N-back Test, and Trail-Making Test-at baseline and at 1 and 4 h post-dosing. The Stanford Sleepiness Scale scores and computerized posturography were also assessed. Results: In the driving simulations, ramelteon and triazolam increased the number of subjects who slid off the road. Triazolam increased the standard deviation of lateral position compared to ramelteon and placebo at 1 h post-dosing. Ramelteon and triazolam significantly increased the time to complete of Trail-Making Test part A and the environmental area in posturography compared to placebo at 1 and 4 h post-dosing. Ramelteon and triazolam significantly increased subjective sleepiness compared to placebo at 1 h post-dosing. Conclusions: Ramelteon may affect road-tracking performance, visual attention and/or psychomotor speed measured by Trail-Making Test part A, and body balance in acute dosing. Lower dose of triazolam also impaired performance worse than ramelteon. Physicians should consider risks and benefits when prescribing both drugs, especially in the initial period of administration. [ABSTRACT FROM AUTHOR]