-
Journal of Psychiatric Research Sep 2020We conducted a random-effects model network meta-analysis to examine differences between lemborexant and suvorexant in efficacy and safety outcomes for treating patients... (Meta-Analysis)
Meta-Analysis
We conducted a random-effects model network meta-analysis to examine differences between lemborexant and suvorexant in efficacy and safety outcomes for treating patients with insomnia. We searched Embase, MEDLINE, and CENTRAL from their inception until April/28/2020. Primary outcomes were subjective time to sleep onset (sTSO), subjective total sleep time (sTST), and subjective wake-after-sleep onset (sWASO) at week 1. Four double-blind, randomized controlled trials were identified (n = 3237; 72.4% female; mean age 58.0 years). The treatment arm consisted of lemborexant 10 mg/d (LEM10, n = 592), lemborexant 5 mg/d (LEM5, n = 589), suvorexant 20/15 mg/d (SUV20/15, n = 493), zolpidem tartrate extended release 6.25 mg/d (ZOL6.25, n = 263), and placebo (n = 1300). All active treatments outperformed placebo regarding sTSO at week 1; standardized mean differences (95% credible interval): LEM10 = -0.51 (-0.63, -0.39), LEM5 = -0.48 (-0.60, -0.36), SUV20/15 = -0.21 (-0.33, -0.10), and ZOL6.25 = -0.30 (-0.46, -0.14); sTST at week 1: LEM10 = -0.58 (-0.70, -0.45), LEM5 = -0.33 (-0.46, -0.21), SUV20/15 = -0.34 (-0.46, -0.23), and ZOL6.25 = -0.42 (-0.59, -0.25); and sWASO at week 1: LEM10 = -0.42 (-0.57, -0.28), LEM5 = -0.26 (-0.40, -0.11), SUV20/15 = -0.18 (-0.32, -0.05), and ZOL6.25 = -0.37 (-0.56, -0.18). Although no significant differences were found in discontinuation due to adverse events between each active drug and placebo, LEM10 and SUV20/15 were associated with greater somnolence compared with placebo. LEM10 had the largest effect size compared with placebo for all primary outcomes, although with a risk of somnolence.
Topics: Azepines; Double-Blind Method; Female; Humans; Male; Middle Aged; Network Meta-Analysis; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles
PubMed: 32531478
DOI: 10.1016/j.jpsychires.2020.05.025 -
The Cochrane Database of Systematic... Nov 2020Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering, and daytime sleepiness are common clinical problems in dementia,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sleep disturbances, including reduced nocturnal sleep time, sleep fragmentation, nocturnal wandering, and daytime sleepiness are common clinical problems in dementia, and are associated with significant carer distress, increased healthcare costs, and institutionalisation. Although non-drug interventions are recommended as the first-line approach to managing these problems, drug treatment is often sought and used. However, there is significant uncertainty about the efficacy and adverse effects of the various hypnotic drugs in this clinically vulnerable population.
OBJECTIVES
To assess the effects, including common adverse effects, of any drug treatment versus placebo for sleep disorders in people with dementia.
SEARCH METHODS
We searched ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group's Specialized Register, on 19 February 2020, using the terms: sleep, insomnia, circadian, hypersomnia, parasomnia, somnolence, rest-activity, and sundowning.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared a drug with placebo, and that had the primary aim of improving sleep in people with dementia who had an identified sleep disturbance at baseline.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data on study design, risk of bias, and results. We used the mean difference (MD) or risk ratio (RR) with 95% confidence intervals (CI) as the measures of treatment effect, and where possible, synthesised results using a fixed-effect model. Key outcomes to be included in our summary tables were chosen with the help of a panel of carers. We used GRADE methods to rate the certainty of the evidence.
MAIN RESULTS
We found nine eligible RCTs investigating: melatonin (5 studies, n = 222, five studies, but only two yielded data on our primary sleep outcomes suitable for meta-analysis), the sedative antidepressant trazodone (1 study, n = 30), the melatonin-receptor agonist ramelteon (1 study, n = 74, no peer-reviewed publication), and the orexin antagonists suvorexant and lemborexant (2 studies, n = 323). Participants in the trazodone study and most participants in the melatonin studies had moderate-to-severe dementia due to Alzheimer's disease (AD); those in the ramelteon study and the orexin antagonist studies had mild-to-moderate AD. Participants had a variety of common sleep problems at baseline. Primary sleep outcomes were measured using actigraphy or polysomnography. In one study, melatonin treatment was combined with light therapy. Only four studies systematically assessed adverse effects. Overall, we considered the studies to be at low or unclear risk of bias. We found low-certainty evidence that melatonin doses up to 10 mg may have little or no effect on any major sleep outcome over eight to 10 weeks in people with AD and sleep disturbances. We could synthesise data for two of our primary sleep outcomes: total nocturnal sleep time (TNST) (MD 10.68 minutes, 95% CI -16.22 to 37.59; 2 studies, n = 184), and the ratio of day-time to night-time sleep (MD -0.13, 95% CI -0.29 to 0.03; 2 studies; n = 184). From single studies, we found no evidence of an effect of melatonin on sleep efficiency, time awake after sleep onset, number of night-time awakenings, or mean duration of sleep bouts. There were no serious adverse effects of melatonin reported. We found low-certainty evidence that trazodone 50 mg for two weeks may improve TNST (MD 42.46 minutes, 95% CI 0.9 to 84.0; 1 study, n = 30), and sleep efficiency (MD 8.53%, 95% CI 1.9 to 15.1; 1 study, n = 30) in people with moderate-to-severe AD. The effect on time awake after sleep onset was uncertain due to very serious imprecision (MD -20.41 minutes, 95% CI -60.4 to 19.6; 1 study, n = 30). There may be little or no effect on number of night-time awakenings (MD -3.71, 95% CI -8.2 to 0.8; 1 study, n = 30) or time asleep in the day (MD 5.12 minutes, 95% CI -28.2 to 38.4). There were no serious adverse effects of trazodone reported. The small (n = 74), phase 2 trial investigating ramelteon 8 mg was reported only in summary form on the sponsor's website. We considered the certainty of the evidence to be low. There was no evidence of any important effect of ramelteon on any nocturnal sleep outcomes. There were no serious adverse effects. We found moderate-certainty evidence that an orexin antagonist taken for four weeks by people with mild-to-moderate AD probably increases TNST (MD 28.2 minutes, 95% CI 11.1 to 45.3; 1 study, n = 274) and decreases time awake after sleep onset (MD -15.7 minutes, 95% CI -28.1 to -3.3: 1 study, n = 274) but has little or no effect on number of awakenings (MD 0.0, 95% CI -0.5 to 0.5; 1 study, n = 274). It may be associated with a small increase in sleep efficiency (MD 4.26%, 95% CI 1.26 to 7.26; 2 studies, n = 312), has no clear effect on sleep latency (MD -12.1 minutes, 95% CI -25.9 to 1.7; 1 study, n = 274), and may have little or no effect on the mean duration of sleep bouts (MD -2.42 minutes, 95% CI -5.53 to 0.7; 1 study, n = 38). Adverse events were probably no more common among participants taking orexin antagonists than those taking placebo (RR 1.29, 95% CI 0.83 to 1.99; 2 studies, n = 323).
AUTHORS' CONCLUSIONS
We discovered a distinct lack of evidence to guide decisions about drug treatment of sleep problems in dementia. In particular, we found no RCTs of many widely prescribed drugs, including the benzodiazepine and non-benzodiazepine hypnotics, although there is considerable uncertainty about the balance of benefits and risks for these common treatments. We found no evidence for beneficial effects of melatonin (up to 10 mg) or a melatonin receptor agonist. There was evidence of some beneficial effects on sleep outcomes from trazodone and orexin antagonists and no evidence of harmful effects in these small trials, although larger trials in a broader range of participants are needed to allow more definitive conclusions to be reached. Systematic assessment of adverse effects in future trials is essential.
Topics: Alzheimer Disease; Azepines; Caregiver Burden; Cognition; Humans; Indenes; Melatonin; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sleep; Sleep Wake Disorders; Time Factors; Trazodone; Triazoles
PubMed: 33189083
DOI: 10.1002/14651858.CD009178.pub4 -
Psychogeriatrics : the Official Journal... Mar 2022Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether... (Meta-Analysis)
Meta-Analysis Review
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).
Topics: Aged; Azepines; Delirium; Humans; Indenes; Randomized Controlled Trials as Topic; Triazoles
PubMed: 34881812
DOI: 10.1111/psyg.12792 -
Journal of Neurology, Neurosurgery, and... Dec 2020To assess the efficacy and safety of Aβ-targeting agents for mild to moderate Alzheimer's disease. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To assess the efficacy and safety of Aβ-targeting agents for mild to moderate Alzheimer's disease.
METHODS
The MEDLINE, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform search portal were searched from their inception to April 2020. We generated pooled estimates using random effects meta-analyses.
RESULTS
Nineteen randomised controlled trials, of which 17 had a low risk of bias, included 12 903 participants. The meta-analysis showed no difference in the cognitive subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog) between anti-Aβ drugs and placebo (mean difference (MD): 0.20, 95% CI -0.40 to 0.81; =99.8%; minimal important difference 3.1-3.8 points, moderate-certainty evidence). For ADAS-Cog, results suggested that one drug that increases Aβ clearance may differ in effect (MD: -0.96, 95% CI -0.99 to -0.92) from drugs that reduce Aβ production (MD: 0.78, 95% CI 0.25 to 1.32) (interaction p<0.000001); this difference also existed in the outcome of MMSE and CDR-SOB. Compared with placebo, anti-Aβ drug-related adverse events were as follows: anxiety, depression, diarrhoea, fatigue, rash, syncope and vomit.
DISCUSSION
From current evidence, anti-Aβ interventions are unlikely to have an important impact on slowing cognitive or functional decline. Although the subgroup analysis suggested possible benefits from Aβ clearance drugs, the analysis has limited credibility, and a benefit from drugs that increase clearance, if real, is very small.
TRIAL REGISTRATION NUMBER
PROSPERO registration number CRD42019126272.
Topics: Acitretin; Alanine; Alzheimer Disease; Amyloid beta-Peptides; Antibodies, Monoclonal, Humanized; Anxiety; Azepines; Clioquinol; Copper; Cyclic S-Oxides; Depression; Diarrhea; Exanthema; Fatigue; Flurbiprofen; Humans; Immunoglobulins, Intravenous; Inositol; Mental Status and Dementia Tests; Minimal Clinically Important Difference; Orotic Acid; Oxadiazoles; Severity of Illness Index; Sulfonamides; Syncope; Thiadiazines; Treatment Outcome; Vomiting
PubMed: 33046560
DOI: 10.1136/jnnp-2020-323497 -
Phytomedicine : International Journal... Nov 2022Securinine is an alkaloid identified from the roots and leaves of the shrub Flueggea suffruticosa (Pall.) Baill. The molecular structure of securinine consists of four... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Securinine is an alkaloid identified from the roots and leaves of the shrub Flueggea suffruticosa (Pall.) Baill. The molecular structure of securinine consists of four rings, including three chiral centers. It has been suggested that securinine can be chemically synthesized from tyrosine and lysine. Securinine has long been used to treat central nervous system diseases. In recent years, more and more evidence shows that securinine also has anticancer activity, which has not been systematically discussed and analyzed.
PURPOSE
This study aims to propose an overall framework to describe the molecular targets of securinine in different signal pathways, and discuss the current status and prospects of each pathway, so as to provide a theoretical basis for the development securinine as an effective anticancer drug.
METHODS
The research databases on the anticancer activity of securinine from PubMed, Scopus, Web of Science and ScienceDirect to 2021 were systematically searched. This paper follows the Preferred Reporting Items and Meta-Analysis guidelines.
RESULTS
Securinine has the ability to kill a variety of human cancer cells, including, leukemia as well as prostate, cervical, breast, lung, and colon cancer cells. It can regulate the signal pathways of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, Wnt and Janus kinase-signal transducer and activator of transcription, promote cancer cell apoptosis and autophagy, and inhibit cancer cell metastasis. Securinine also has the activity of inducing leukemia cell differentiation.
CONCLUSION
Although there has been some experimental evidence indicating the anticancer effect of securinine and its possible pharmacology, in order to design more effective anticancer drugs, it is necessary to study the synergy of intracellular signaling pathways. More in vivo experiments and even clinical studies are needed, and the synergy between securinine and other drugs is also worth studying.
Topics: Alkaloids; Azepines; Cell Line, Tumor; Heterocyclic Compounds, Bridged-Ring; Humans; Janus Kinases; Lactones; Leukemia; Lysine; Male; Phosphatidylinositols; Piperidines; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Tyrosine
PubMed: 36063584
DOI: 10.1016/j.phymed.2022.154417 -
Epilepsy Research Nov 2023The use of zebrafish as a model organism is gaining evidence in the field of epilepsy as it may help to understand the mechanisms underlying epileptic seizures. As...
The use of zebrafish as a model organism is gaining evidence in the field of epilepsy as it may help to understand the mechanisms underlying epileptic seizures. As zebrafish assays became popular, the heterogeneity between protocols increased, making it hard to choose a standard protocol to conduct research while also impairing the comparison of results between studies. We conducted a systematic review to comprehensively profile the chemically-induced seizure models in zebrafish. Literature searches were performed in PubMed, Scopus, and Web of Science, followed by a two-step screening process based on inclusion/exclusion criteria. Qualitative data were extracted, and a sample of 100 studies was randomly selected for risk of bias assessment. Out of the 1058 studies identified after removing duplicates, 201 met the inclusion criteria. We found that the most common chemoconvulsants used in the reviewed studies were pentylenetetrazole (n = 180), kainic acid (n = 11), and pilocarpine (n = 10), which increase seizure severity in a dose-dependent manner. The main outcomes assessed were seizure scores and locomotion. Significant variability between the protocols was observed for administration route, duration of exposure, and dose/concentration. Of the studies subjected to risk of bias assessment, most were rated as low risk of bias for selective reporting (94%), baseline characteristics of the animals (67%), and blinded outcome assessment (54%). Randomization procedures and incomplete data were rated unclear in 81% and 68% of the studies, respectively. None of the studies reported the sample size calculation. Overall, these findings underscore the need for improved methodological and reporting practices to enhance the reproducibility and reliability of zebrafish models for studying epilepsy. Our study offers a comprehensive overview of the current state of chemically-induced seizure models in zebrafish, highlighting the common chemoconvulsants used and the variability in protocol parameters. This may be particularly valuable to researchers interested in understanding the underlying mechanisms of epileptic seizures and screening potential drug candidates in zebrafish models.
Topics: Animals; Zebrafish; Reproducibility of Results; Anticonvulsants; Seizures; Epilepsy; Pentylenetetrazole
PubMed: 37801749
DOI: 10.1016/j.eplepsyres.2023.107236 -
Journal of Critical Care Oct 2020To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization.
PURPOSE
To assess the efficacy and safety of suvorexant for the prevention of delirium during acute hospitalization.
MATERIALS AND METHODS
Pubmed (1946 to December 2019) and Embase (1947 to December 2019) were queried using the search term combination: delirium, confusion, cognitive defect, encephalopathy, critically ill patient, critical illness, or hospitalization and suvorexant or orexin receptor antagonist. Studies analyzed for relevance evaluated clinical outcomes of patients treated with suvorexant for prevention of delirium. Studies appropriate to the objective were evaluated, including two randomized controlled trials and four retrospective studies.
RESULTS
In acutely hospitalized patients, treatment with suvorexant 15 to 20 mg alone or in combination with ramelteon resulted in a reduction in development of delirium, time until delirium onset, and length of hospital stay. When assessed, suvorexant was well tolerated and adverse effects were no worse than placebo.
CONCLUSION
Based on the reviewed literature, suvorexant has shown positive outcomes in the prevention of delirium during an acute hospitalization. Larger trials comparing the efficacy of suvorexant to other sleep modulating options are necessary to further delineate its role for the prevention of delirium.
Topics: Aged; Aged, 80 and over; Azepines; Critical Care; Critical Illness; Delirium; Drug Therapy, Combination; Female; Humans; Indenes; Length of Stay; Male; Middle Aged; Orexin Receptor Antagonists; Randomized Controlled Trials as Topic; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Retrospective Studies; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles
PubMed: 32480359
DOI: 10.1016/j.jcrc.2020.05.006 -
Sleep Medicine Reviews Oct 2020Orexin receptor antagonists are a relatively new hypnotic principle. Their influence on human sleep architecture is a point of debate that has not been systematically...
Orexin receptor antagonists are a relatively new hypnotic principle. Their influence on human sleep architecture is a point of debate that has not been systematically evaluated. Thus, we performed a systematic review to assess how these compounds effect sleep architecture in healthy and clinical human samples. Relevant articles were identified via searches of PubMed, Embase, the Cochrane central register of controlled trials, and clinicaltrials. gov. From 1147 retrieved records, 18 satisfied inclusion criteria and formed the basis of this review. Of these, fifteen studies administered dual orexin receptor antagonists (DORA) in a healthy control (five studies) or clinical sample (ten studies). By contrast, three studies administered selective orexin receptor-2 antagonists (2-SORA) in either a healthy control (one study) or clinical sample (two studies). Results reveal DORAs increase total sleep time primarily by promoting REM sleep, without affecting, or even decreasing, non-REM sleep, especially in clinical samples. Therefore, the clinical utility of DORAs may depend on the specific sample being treated. For 2-SORAs, limited evidence available precludes firm conclusions about their influence on human sleep architecture and, thus, further investigation of 2-SORAs is required to define their effects and make comparisons on this basis with DORAs.
Topics: Azepines; Healthy Volunteers; Humans; Orexin Receptor Antagonists; Polysomnography; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Stages; Sleep, REM; Triazoles
PubMed: 32505969
DOI: 10.1016/j.smrv.2020.101332