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Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep–wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow‐wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA‐approved medications for delirium or delirium‐related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non‐pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re‐regulation of sleep–wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision‐making regarding these interventions. [ABSTRACT FROM AUTHOR]

Many selective synthetic melatonin receptor agonists have anticonvulsant/anti-epileptogenic properties. These agonists bind to melatonin receptor 1 (MT1) and receptor 2 (MT2), causing their activation. Therefore, we evaluated the anticonvulsant effect of Ramelteon (RMLT) as a melatonin agonist in the PTZ (Pentylenetetrazol)- kindling model. In the study, 36 male Wistar Albino rats were assessed in 6 groups (Sham, PTZ, dimethylsulphoxide (DMSO), Valproic acid (VPA) (150 mg/kg) + PTZ, RMLT (30 mg/kg)+PTZ, VPA+RMLT+PTZ). Cortical electroencephalography (EEG) data were recorded for all groups. Seizures were scored according to the Racine scale. Seizure scores and onset times of the first myoclonic movements were compared in EEG traces. Total antioxidant status (TAS), total oxidant status (TOS), catalase, myeloperoxidase (MPO), and Thiol levels were measured in serum samples. Also, Calcineurin (CaN), Neuropeptide-Y (NPY), Neuron Specific Enolase (NSE), and S100B levels were measured in brain tissue samples. There was a significant difference between the PTZ and PTZ+Valproic acid+RMLT groups for the onset of the first myoclonic movements and the rate of spikes in the EEG traces in Racine's convulsion stages (P<0.001). Biochemical parameters were not significant between the groups (P > 0.05). RMLT has anticonvulsant properties. Additionally, the receptor preference of RMLT can be investigated. [ABSTRACT FROM AUTHOR]

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]

Abstract 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.

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]

Abstract\nHIGHLIGHTSRamelteon (RMLT) is a melatonin receptor agonist that it has antioxidative and anti-inflammatory effects associated with DNA damage through different mechanisms of action. In this regard, we investigated the potential usefulness of RMLT as a protective agent against methotrexate (MTX)-induced DNA damage. Four groups were constituted from 32 Wistar albino rats: Negative control, RMLT, MTX, and MTX + RMLT. Twenty mg/kg MTX (i.p., single dose) and RMLT 10 mg/kg (oral, 7 days) was administered. Comet assay was used and the parameter %TailDNA was used to detect DNA damage. %TailDNA was 4.90 ± 0.19 in the control group, 7.85 ± 0.33 in the MTX group, 5.49 ± 0.24 in the RMLT group, and 5.86 ± 0.23 in the MTX + RMLT group. While there was a significant increase in DNA damage in the MTX-treated group compared to the control group, there was a significant reduction in DNA damage in the MTX + RMLT group, compared to the MTX group (p < 0.001). In conclusion, it was observed that combined treatment with RMLT significantly reduced MTX-induced DNA damage. Investigate the possible protective effect of RMLT against DNA damage caused by MTX using the comet method.The DNA damage of RMLT treated group was significantly reduced compared to group and MTX group. (p < 0.001).Combined treatment with MTX significantly reduces MTX-induced DNA damage.Investigate the possible protective effect of RMLT against DNA damage caused by MTX using the comet method.The DNA damage of RMLT treated group was significantly reduced compared to group and MTX group. (p < 0.001).Combined treatment with MTX significantly reduces MTX-induced DNA damage. [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]

Neurodegenerative and psychiatric diseases remain a therapeutic challenge. Mental illnesses such as depression and bipolar affective disorder lead to disruption of the diurnal rhythm of melatonin secretion and disruption of the sleep-wake axis. The use of new melatonergic drugs has received special attention in recent years. Selective melatoninergic M1 and M2 receptor agonists (tasimelteon, ramelteon) show a more favorable metabolic profile, better regulation of circadian rhythms, and effects on total sleep time and sleep quality compared to the already well-studied melatonin. In addition, these drugs show no addictive potential. Agomelatine, through its action on M1 and M2 receptors, as well as serotonergic 5-HT2C and 5-HT2B receptors, exhibits antidepressant, normothymic, and neuroprotective effects, providing primary therapy or adjunctive treatment.

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]

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]

OBJECTIVE: To explore the protective effect and mechanism of Ramelteon on lipopolysaccharide ( LPS )-induced increased permeability of blood-brain barrier ( BBB ) model, as well as its relationship with inflammatory and oxidative stress responses. METHODS: Twenty-four healthy C57BL / 6 male mice were divided into the control group (0. 9% sodium chloride solution), Ramelteon group, LPS group and LPS+Ramelteon group. The blood brain barrier injury of mice was induced by LPS and the endothelial cell injury was stimulated. Brain permeability was assessed by using the Evans blue staining method, while cell viability was determined by utilizing the cell counting kit-8 (CCK-8). Expression of human tight junction protein 1 (ZO-1) and occludin in brain tissue and endothelial cells was evaluated through immunostaining and Western blotting. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay were employed to measure the levels of inflammatory factor interleukin-1β ( IL-1β) and monocyte chemotactic protein 1 ( MCP-1). Malondialdehyde (MDA) concentration in brain tissue and endothelial cells was detected by using the thiobarbituric acid method. Expression of human nuclear factor E2 related factor 2 (Nrf2) and quinone oxidoreductase (NQO1) in the cell nucleus was determined via Western blotting. RESULTS: (1) Compared to the control group, mice in the LPS group showed increased brain permeability and significantly decreased neurological function scores. In comparison to the LPS group, mice in the LPS + Ramelteon group exhibited decreased brain permeability and significantly increased neurological function scores,with statistically significant difference (P< 0. 05). (2) Compared with the control group, the LPS group displayed decreased expression of ZO-1 and Occludin, along with increased expression of IL-1β and MCP-1; compared with the LPS group, the LPS+Ramelteon group showed increased expression of ZO-1 and Occludin, and decreased expression of IL-1β and MCP-1, the differences were statistically significant (P<0. 05). (3) Compared with the control group, the LPS group showed decreased expression of Nrf2 and NQO1, and increased levels of MDA; compared with the LPS group, the expression of Nrf2 and NQO1 in LPS+Ramelteon group increased, while the level of MDA decreased, with statistically significant differences (P<0. 05). (4) Compared with the control group, b End. 3 endothelial cell viability decreased, permeability increased significantly, and expression levels of ZO-1 and Occludin were significantly down regulated in the LPS group, with statistically significant differences (P<0. 05). Conversely, the LPS + Ramelteon group showed increased endothelial cell viability, decreased permeability, and significantly increased expression levels of ZO-1 and Occludin, which were positively correlated with the dose of Ramelteon, with statistically significant differences (P<0. 05). (5) Compared with the control group, LPS group significantly inhibited the expression levels of Nrf2 and NQO1; compared with the LPS group, the expression level of Nrf2 increased in the LPS +Ramelteon group, and was positively correlated with the dose of Ramelteon, with statistically significant differences (P <0. 05). (6) Both Compound C and si-Nrf2 could inhibit the activating AMP-activated protein kinase (AMPK) / Nrf2 signaling pathway, inducing oxidative stress and weakening the protective effect of Ramelteon on the reduction of ZO-1 and Occludin induced by LPS and the increase in endothelial monolayer permeability. CONCLUSIONS: Ramelteon can improve LPS-induced increased permeability of blood-brain barrier in vitro by activating AMPK-Nrf2 signaling pathway, and its mechanism may be related to inhibiting inflammatory and oxidative stress responses. [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]

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]

Abstract 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.

Introduction Chronic insomnia affects 5% to 10% of the US population, increasing the demand for treatment options and the corresponding research to prove their validity.1 This review compares recommendations from 3 clinical guidelines and summarizes hypnotic medications, including their newly reported side effects not mentioned in the guidelines. In addition, we aim to provide an overview of what pharmacotherapies are available for prescribers and patients. Methods A literature search was conducted for articles published prior to January 10, 2022, and case reports and clinical studies were retrieved from PubMed and Google Scholar. Results Definitive conclusions cannot be drawn regarding the safety and efficacy of medications reviewed; however, trends are apparent. All 3 guidelines included in this review remarked most treatment recommendations as weak except for cognitive behavioral therapy for insomnia, which is effective but not readily available. Furthermore, based on the 15 case reports and 13 clinical studies presented in this review, many of the medications used for treatment of insomnia present safety concerns. Discussion Benzodiazepines and benzodiazepine receptor agonists are commonly used hypnotic agents with the “Z-drugs” having robust data establishing their efficacy for the short-term treatment of chronic insomnia. However, significant adverse effects related to the central nervous system (CNS), including developing tolerance, addiction, CNS depression, and amnesia, remain barriers to their long-term use. In comparison, newer agents present more favorable side-effect profiles although with less established efficacy. Additionally, off-label agents, including antidepressants, antihistamines, and natural supplements, are discussed due to their prominent use.

Abstract Background Benzodiazepines, such as flunitrazepam, may be at risk of disinhibition, leading to aggressiveness, impulsivity, self‐harm, and possibly suicide attempts, whereas ramelteon may be far from disinhibition. Case Presentation In a 43‐year‐old female with primary insomnia, flunitrazepam alone did not induce any type of disinhibition, but the addition of ramelteon to flunitrazepam brought about disinhibition, leading to aggressiveness and finally to her suicide attempt. Her disinhibition rapidly subsided as soon as ramelteon alone was discontinued. Conclusion These findings suggest that a suicide attempt may occur during ramelteon and flunitrazepam combination in a susceptible patient.

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]

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]

Ramelteon is used to ameliorate sleep disorders that negatively affect memory performance; however, it remains unknown whether ramelteon strengthens neutral memories, which do not involve reward or punishment. To address this, we monitored behavior of mice treated with vehicle/ramelteon while they performed a novel object recognition task and a spontaneous alternation task. Object memory performance in the novel object recognition task was improved only if ramelteon was injected before training, suggesting that ramelteon specifically enhances the acquisition of object recognition memory. Ramelteon also enhanced spatial working memory in the spontaneous alternation task. Altogether, acute ramelteon treatment enhances memory in quasi-natural contexts.

INTRODUCTION: Sepsis is a life-threatening excessive systemic inflammatory reaction syndrome to infection that usually occurs in patients with bacteremia. The respiratory system is one of the structures most affected by acute organ damage. Melatonin plays an important role in regulating various physiological functions of the body, including antioxidant and anti-inflammatory. Ramelteon (RAME) is the first melatonin receptor agonist confirmed for clinical use. The goal of this study is to determine the effects of RAME on endotoxin-induced septic lung injury in rats. METHODS: Thirty-two female rats were separated randomly into four groups (n=8). Group healthy received intraperitoneal normal saline, group sepsis received intraperitoneally 10 mg/kg lipopolysaccharide (LPS), group sepsis+RAME2 received 10 mg/kg LPS plus 2mg/kg RAME, and group sepsis+RAME4 received 10 mg/kg LPS plus 4mg/kg RAME. RAME was administered by oral gavage 1 hour before LPS administration. The lung tissues were collected 12 hours after LPS administration and investigated molecularly (qRT-PCR analyses of Tumor Necrosis Factor-α, nuclear factor kappa-β, and interleukin 1-beta mRNA expression) and histopathologically (staining with Harris Hematoxylin and Eosin Y). RESULTS: TNF-α, NF-κβ, and IL-1β levels significantly decreased dose-dependent in the septic rats following RAME administration. RAME administration ameliorated histopathological injury in lung tissues due to sepsis. DISCUSSION AND CONCLUSION: RAME ameliorated the inflammatory response in endotoxin-induced sepsis. These findings suggest that RAME can be a promising agent by contributing to alternative preventive treatment methods for sepsis with its anti-inflammatory effect.

The possible effects of ramelteon, a melatonin receptor agonist on bleomycin-induced lung fibrosis were analyzed via transforming growth factor β1 (TGF-β1), the high mobility group box 1 (HMGB1) and Nod-like receptor pyrin domain-containing 3 (NLRP3) which are related to the fibrosis process. Bleomycin (0.1 ​mL of 5 ​mg/kg) was administered by intratracheal instillation to induce pulmonary fibrosis (PF). Starting 24 ​h after bleomycin administration, a single dose of ramelteon was administered by oral gavage to the healthy groups, i.e. PF ​+ ​RM2 (pulmonary fibrosis model with bleomycin ​+ ​ramelteon at 2 ​mg/kg) and PF ​+ ​RM4 (pulmonary fibrosis model with bleomycin ​+ ​ramelteon at 4 ​mg/kg) at 2 and 4 ​mg/kg doses, respectively. Real-time polymerase chain reaction (real-time PCR) analyses, histopathological, and immunohistochemical staining were performed on lung tissues. Lung tomography images of the rats were also examined. The levels of TGF-β1, HMGB1, NLRP3, and interleukin 1 beta (IL-1β) mRNA expressions increased as a result of PF and subsequently decreased with both ramelteon doses (p ​< ​0.0001). Both doses of ramelteon partially ameliorated the reduction in the peribronchovascular thickening, ground-glass appearances, and reticulations, and the loss of lung volume. The severity of fibrosis decreased with ramelteon application. These effects of ramelteon may be associated with NLRP3 inflammation cascade. [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]

Objective:Methotrexate (MTX), a drug used in the treatment of autoimmune diseases and cancers, is a folic acid antagonist, but it has toxic effects on the gastrointestinal system (GIS). In this study, we examined the anti-inflammatory, antioxidant and anti-apoptotic effects of Ramelteon (RAM), a melatonin receptor agonist, on the MTX-induced toxicity in the intestinal tissue of rats.Methods:Thirty-two male Wistar albino rats were randomly divided into 4 groups; Control group, MTX group, MTX + RAM group, and RAM group. Single-dose 0.1 mL 20 mg/kg MTX, saline or 0.1 mL 10 mg/kg RAM orally was administered for 7 days. Animals were sacrificed at the end of 7 days after the last drug administration. Then, intestinal tissues were collected for biochemical, histopathological and immunohistochemical analyses.Results:While normal histological findings and biochemical parameters were observed in the control and RAM groups, in the MTX group, mononuclear cell infiltrations, hemorrhagic areas, degenerations in the submucosa and Lieberkuhn crypts were observed in the intestinal sections. Caspase-3 (Cas-3) and tumor necrosis factor-alpha (TNF-α) expressions, total oxidant status (TOS) and oxidative stress index (OSI) increased and total antioxidant status (TAS) decreased in the MTX group. RAM treatment decreased Cas-3 and TNF-α expressions, TOS, OSI levels and increased TAS levels.Conclusion:In this study, RAM showed anti-apoptotic, antioxidant and anti-inflammatory effects on MTX-induced toxicity in intestinal tissue. Therefore, it was suggested that RAM might be used in MTX-like toxicities to alleviate the side effects on the GIS.

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.

Objective Despite the advances in medicine, sepsis still remains a major health problem worldwide and brain tissue is one of the structures damaged in the early period of sepsis. Neuroinflammation (NI) is considered as the main mechanism in septic brain injury. Ramelteon (RML) is a non-selective (MT1 / MT2) melatonin receptor agonist and was approved by the FDA in 2005 with the indication of insomnia. RML shows relatively higher affinity for both receptor subtypes among other melatonergic agonist drugs. Material and Method Twenty-eight male Wistar Albino rats were used to investigate the protective effect of RML on lipopolysaccharide (LPS) induced NI. Control, LPS (5 mg/kg, intraperitoneally), RML (8 mg/kg, orally) and LPS + RML (45 minutes before LPS) groups were created. Six hours following the last drug administration, rats were sacrificed. Blood for hemogram analysis and cortical and hippocampal tissues for histopathological evaluation were collected. Results LPS increased white blood cell and neutrophil/ lymphocyte ratio (NLR) while it decreased lymphocyte and platelet counts. RML decreased NLR and increased platelet counts significantly. In histochemical evaluation, marked inflammatory cell infiltration and apoptosis were observed in both hippocampal and cortical areas of LPS group. RML decreased the inflammatory response and apoptotic bodies in these areas. Conclusion RML may be protective on LPS-induced NI observed in hippocampus via anti-inflammatory and anti-apoptotic mechanisms. [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.)

OBJECTIVES:To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. DESIGN:Parallel-arm, randomized, double-blinded, placebo-controlled trial. SETTING:Academic medical center in La Jolla, California. PATIENTS:Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. INTERVENTIONS:Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. MEASUREMENTS AND MAIN RESULTS:Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively. CONCLUSIONS:Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

Introduction and objective Melatonin is the most important compound produced by the pineal gland. Its daily secretion cycle is responsible for the normal rhythm of sleep and wakefulness. The aim of the study was to analyse the clinical application of melatonin and melatonin receptor agonists MT1 and MT2 in the treatment of sleep disorders and depression. Review methods A literature review was performed by searching electronic databases, such as PubMed, Scopus, Google Scholar, Web of Science, entering key words ‘melatonin’, ‘ramelteon’, ‘tasimelteon’, ‘sleep disorders’ in Polish and English. Brief description of the state of knowledge The action of melatonin is determined by its agonistic effect on the melatonin receptors MT1 and MT2. Darkness stimulates the synthesis of this hormone, and the suprachiasmatic nuclei of the hypothalamus (SCN) are responsible for regulation of melatonin secretion. The appearance of melatonin production disorders is a phenomenon observed most frequently in elderly people, the blind, those undertaking shift work or travelling intercontinentally. In addition to melatonin, other MT1 and MT2 receptor agonists such as ramelteon, tasimelteon or agomelatine are used in the treatment of sleep disorders. However, the latter is used primarily as an antidepressant, due to its additional antagonistic effect on serotonin 5-HT2C receptors. Summary Abnormalities of melatonin secretion can lead to sleep disorders, as well as other conditions throughout the body. Melatonin receptor agonists are recognised as relatively well tolerated and safe, and their use may be considered in a wide range of patients.

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]

Pharmaceutical care is important for mental health during the perinatal period, which is often characterized by insomnia. In recent years, prescriptions of melatonin receptor agonists (MRAs) and dual orexin receptor antagonists (DORAs) for insomnia have increased; however, their use during the perinatal period has scarcely been reported. In the present study, we developed a UPLC-MS/MS method for the quantification of ramelteon, its metabolite M-II, suvorexant, and lemborexant in human plasma and breast milk to accumulate information on the safety and transfer of MRAs and DORAs into breast milk. Samples of MRAs (ramelteon and M-II) in plasma and breast milk were prepared using liquid–liquid extraction (LLE) with ethyl acetate. For DORAs (suvorexant and lemborexant), LLE with ethyl acetate was applied to plasma samples. For breast milk samples, significant ion suppression was observed for LLE with ethyl acetate. Solid-phase extraction (SPE) cartridges capable of removing phospholipids improved the matrix effects. Finally, protein precipitation with methanol and an SPE cartridge, InertSep® Phospholipid Remover, were selected for breast milk sample preparation. An ACQUITY UPLC BEH C18 column was used for analyte separation. MRAs and DORAs were eluted using isocratic and gradient elution, respectively, and analyzed using electrospray ionization in the positive mode with multiple reaction monitoring. The range of calibration curve for MRAs and DORAs was 0.1–25 and 0.5–50 ng/ml, respectively. Both the plasma and breast milk samples exhibited good linearity over this range. The method was validated by evaluating its accuracy and precision, matrix effect, recovery, carry-over, stability, and dilution integrity. The validated method was successfully applied to clinical samples donated by breastfeeding women and the milk/plasma (M/P) ratio and relative infant dose (RID) of lemborexant (one case) and suvorexant (two cases) were estimated. The M/P ratio of lemborexant was <1, and the RID was 1.05 %. The M/P ratio of suvorexant was <0.1, and RID was 0.11–0.20 %. This method will be useful for future studies evaluating the safety of these drugs during breastfeeding. ● A UPLC-MS/MS method was devised for MRA and DORA in plasma and breast milk. ● Sample preparation procedures were established considering the matrix effect. ● The method was successfully applied to quantitate DORAs in clinical samples. ● The M/P ratios and RIDs of DORAs were estimated from the quantified data. [ABSTRACT FROM AUTHOR]

Melatonin is a neurohormone that acts at the suprachiasmatic nucleus to diminish the wake-promoting signal of the circadian clock and induce sleepiness. Exogenous melatonin is available as an over-the-counter supplement to induce sleepiness with 1.3% of adults reporting melatonin use in the past 30 days in 2012. Melatonin is also a frequently used treatment for sleep disturbances in the traumatic brain injury (TBI) population, however, evidence of melatonin efficacy for disordered sleep in this population is scarce. This article reviews the evidence regarding melatonin or melatonin receptor agonists used for sleep disorders in the TBI population. A literature search was performed using PubMed, Embase, Ovid MEDLINE, Cochrane Library, and Google Scholar. In total, four clinical randomized controlled trials were summarized and graded based on the American Academy of Neurology clinical practice guidelines. The evidence that exists suggests melatonin or melatonin receptor agonists improve some aspects of sleep in the TBI population. Additional high-quality studies investigating how melatonin affects the sleep and functional recovery of individuals with TBIs are needed.

Objective: Methotrexate (MTX), a drug used in the treatment of autoimmune diseases and cancers, is a folic acid antagonist, but it has toxic effects on the gastrointestinal system (GIS). In this study, we examined the anti-inflammatory, antioxidant and anti-apoptotic effects of Ramelteon (RAM), a melatonin receptor agonist, on the MTX-induced toxicity in the intestinal tissue of rats. Methods: Thirty-two male Wistar albino rats were randomly divided into 4 groups; Control group, MTX group, MTX + RAM group, and RAM group. Single-dose 0.1 mL 20 mg/kg MTX, saline or 0.1 mL 10 mg/kg RAM orally was administered for 7 days. Animals were sacrificed at the end of 7 days after the last drug administration. Then, intestinal tissues were collected for biochemical, histopathological and immunohistochemical analyses. Results: While normal histological findings and biochemical parameters were observed in the control and RAM groups, in the MTX group, mononuclear cell infiltrations, hemorrhagic areas, degenerations in the submucosa and Lieberkuhn crypts were observed in the intestinal sections. Caspase-3 (Cas-3) and tumor necrosis factor-alpha (TNF-α) expressions, total oxidant status (TOS) and oxidative stress index (OSI) increased and total antioxidant status (TAS) decreased in the MTX group. RAM treatment decreased Cas-3 and TNF-α expressions, TOS, OSI levels and increased TAS levels. Conclusion: In this study, RAM showed anti-apoptotic, antioxidant and anti-inflammatory effects on MTX-induced toxicity in intestinal tissue. Therefore, it was suggested that RAM might be used in MTX-like toxicities to alleviate the side effects on the GIS. [ABSTRACT FROM AUTHOR]

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]

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]

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.)