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Ageing Research Reviews Sep 2021Intervertebral disc degeneration (IDD) is a common degenerative disease of the musculoskeletal system that develops with age. It is regarded as the main cause of chronic... (Review)
Review
Intervertebral disc degeneration (IDD) is a common degenerative disease of the musculoskeletal system that develops with age. It is regarded as the main cause of chronic low back pain in the elderly. IDD has various causes, including ageing, mechanical overloading, and nutritional deficiency. Melatonin is a pleiotropic indole hormone secreted by the pineal gland and plays an important role in resisting various degenerative diseases. The serum levels of melatonin decline with age and are reported to be negatively correlated with the symptomatic and histopathological scores of IDD. In vivo studies have shown that exogenous administration of melatonin could maintain the structural integrity of the intervertebral disc and inhibit the development of IDD. Mechanistically, by interacting with its membrane or intracellular receptors, melatonin can promote autophagic flux, scavenge free radicals, inhibit the release of pro-inflammatory factors, and block apoptotic pathways, thereby enhancing anti-stress abilities and matrix anabolism in different types of disc cells. Therefore, melatonin supplementation may be a promising therapeutic strategy for IDD. This review aimed to summarize the latest findings regarding the therapeutic potential of melatonin in IDD.
Topics: Aged; Humans; Intervertebral Disc; Intervertebral Disc Degeneration; Melatonin; Nucleus Pulposus
PubMed: 34139338
DOI: 10.1016/j.arr.2021.101394 -
Pediatrics Jun 2021Functional abdominal pain disorders (FAPDs) are common in childhood, impacting quality of life and school attendance. There are several compounds available for the...
CONTEXT
Functional abdominal pain disorders (FAPDs) are common in childhood, impacting quality of life and school attendance. There are several compounds available for the treatment of pediatric FAPDs, but their efficacy and safety are unclear because of a lack of head-to-head randomized controlled trials (RCTs).
OBJECTIVE
To systematically review the efficacy and safety of the pharmacologic treatments available for pediatric FAPDs.
DATA SOURCES
Electronic databases were searched from inception to February 2021.
STUDY SELECTION
RCTs or systematic reviews were included if the researchers investigated a study population of children (4-18 years) in whom FAPDs were treated with pharmacologic interventions and compared with placebo, no treatment, or any other agent.
DATA EXTRACTION
Two reviewers independently performed data extraction and assessed their quality. Any interresearcher disagreements in the assessments were resolved by a third investigator.
RESULTS
Seventeen articles representing 1197 children with an FAPD were included. Trials investigating antispasmodics, antidepressants, antibiotics, antihistaminic, antiemetic, histamine-2-receptor antagonist, 5-HT4-receptor agonist, melatonin, and buspirone were included. No studies were found on treatment with laxatives, antidiarrheals, analgesics, antimigraines, and serotonergics.
LIMITATIONS
The overall quality of evidence on the basis of the Grading of Recommendations, Assessment, Development and Evaluations system was very low to low.
CONCLUSIONS
On the basis of current evidence, it is not possible to recommend any specific pharmacologic agent for the treatment of pediatric FAPDs. However, agents such as antispasmodics or antidepressants can be discussed in daily practice because of their favorable treatment outcomes and the lack of important side effects. High-quality RCTs are necessary to provide adequate pharmacologic treatment. For future intervention trials, we recommend using homogenous outcome measures and instruments, a large sample size, and long-term follow-up.
Topics: Abdominal Pain; Child; Drug-Related Side Effects and Adverse Reactions; Humans; Treatment Outcome
PubMed: 34045320
DOI: 10.1542/peds.2020-042101 -
International Journal of Molecular... Apr 2021Myeloid differentiation 88 (MyD88) is a well-established inflammatory adaptor protein. It is one of the essential downstream proteins of the toll-like receptor 4 (TLR4)...
Myeloid differentiation 88 (MyD88) is a well-established inflammatory adaptor protein. It is one of the essential downstream proteins of the toll-like receptor 4 (TLR4) signaling pathway. TLRs are pattern recognition receptors that are usually activated by the damage-associated molecular pattern molecules (DAMPs). Sterile inflammation is triggered by the endogenous DAMPs released in response to global cerebral ischemia and from extravasated blood after subarachnoid hemorrhage (SAH). In this review, we highlight the importance of the neuroinflammatory role of the MyD88 in the SAH. We also explore a few possible pharmacological agents that can be used to decrease SAH-associated neuroinflammation by modulating the MyD88 dependent functions. Pharmacological agents such as flavonoids, melatonin, fluoxetine, pentoxifylline and progesterone have been investigated experimentally to reduce the SAH-associated inflammation. Inhibition of the MyD88 not only reduces the expression of pro-inflammatory cytokines, but also potentially inhibits other processes that can augment the SAH associated inflammation. Further investigations are required to translate these findings in the clinical setting.
Topics: Animals; Humans; Inflammation; Myeloid Differentiation Factor 88; Receptors, Pattern Recognition; Subarachnoid Hemorrhage
PubMed: 33919485
DOI: 10.3390/ijms22084185 -
European Archives of Psychiatry and... Aug 2021The objective is to understand genetic predisposition to delirium. Following PRISMA guidelines, we undertook a systematic review of studies involving delirium and... (Meta-Analysis)
Meta-Analysis
The objective is to understand genetic predisposition to delirium. Following PRISMA guidelines, we undertook a systematic review of studies involving delirium and genetics in the databases of Pubmed, Scopus, Cochrane Library and PsycINFO, and performed a meta-analysis when appropriate. We evaluated 111 articles, of which 25 were finally included in the analysis. The studies were assessed by two independent researchers for methodological quality using the Downs and Black Tool and for genetic analysis quality. We performed a meta-analysis of 10 studies of the Apolipoprotein E (APOE) gene, obtaining no association with the presence of delirium (LOR 0.18, 95% CI - 0.10-0.47, p = 0.21). Notably, only 5 out of 25 articles met established criteria for genetic studies (good quality) and 6 were of moderate quality. Seven studies found an association with APOE4, the dopamine transporter gene SCL6A3, dopamine receptor 2 gene, glucocorticoid receptor, melatonin receptor and mitochondrial DNA haplotypes. One genome-wide association study found two suggestive long intergenic non-coding RNA genes. Five studies found no association with catechol-o-methyltransferase, melatonin receptor or several interleukins genes. The studies were heterogenous in establishing the presence of delirium. Future studies with large samples should further specify the delirium phenotype and deepen our understanding of interactions between genes and other biological factors.
Topics: Delirium; Genetic Predisposition to Disease; Humans
PubMed: 33779822
DOI: 10.1007/s00406-021-01255-x -
Journal of Psychiatric Research Jan 2021Melatonin, a pineal gland hormone is reported to have a protective effect against delirium. This systematic review and meta-analysis explores the effect of melatonin and... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Melatonin, a pineal gland hormone is reported to have a protective effect against delirium. This systematic review and meta-analysis explores the effect of melatonin and melatonin receptor agonist, ramelteon on delirium prevention in adult hospitalized patients.
METHODS
Randomized Controlled trials of melatonin/ramelteon published up to May 7, 2020 were identified from MEDLINE, PREMEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled trials, PubMed, and Google Scholar. The primary outcome was delirium incidence. The secondary outcomes were sleep quality, sedation score, sedatives requirement, delirium duration, length of hospital stay, length of Intensive Care Unit (ICU) stay, mortality and adverse events. A meta-analysis with a random-effects models was performed. Estimates were presented as Risk Ratio (RR) or Mean Differences (MD) with 95% Confidence Interval (CI).
FINDINGS
Fourteen studies with 1712 participants were included. Melatonin/ramelteon significantly reduced delirium incidence (RR 0·61, 95% CI 0·42-0·89, p 0·009) with risk reduction of 49% in surgical patients and 34% in ICU patients. Non-significant reduction was found in medical patients. Melatonin/ramelteon were associated with improvement in sleep quality, increased sedation score and lower sedatives consumption. However, they did not reduce delirium duration, length of hospital stay, length of ICU stay and mortality. Hallucinations, nightmares and gastrointestinal disorders were prevalent in melatonin group.
INTERPRETATION
Melatonin/ramelteon are associated with reduction in delirium incidence in hospitalized patients. However, this effect seems confined to surgical and ICU patients. The optimum dosage and formulation of melatonin, and treatment duration remain uncleared and open to further studies with larger sample sizes.
Topics: Adult; Delirium; Humans; Hypnotics and Sedatives; Intensive Care Units; Length of Stay; Melatonin
PubMed: 33348252
DOI: 10.1016/j.jpsychires.2020.12.020 -
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 -
The Science of the Total Environment Mar 2021With the unprecedented urbanization light pollution has emerged as a ubiquitous problem, and there has been accumulating evidence on the links between exposure to light... (Meta-Analysis)
Meta-Analysis
BACKGROUND
With the unprecedented urbanization light pollution has emerged as a ubiquitous problem, and there has been accumulating evidence on the links between exposure to light at night (LAN) and breast cancer risk. We conducted a systematic review and meta-analysis of published studies on the associations between LAN exposure and breast cancer risk.
METHODS
We included all observational human studies wherein the exposure variable was LAN measured in indoor and outdoor environments, and the outcome was breast cancer. We employed summary relative risks (SRR) for breast cancer by comparing highest versus lowest categories of LAN exposure within a random-effects model. The National Toxicology Program's (NTP) Office of Health Assessment and Translation (OHAT) risk of bias rating tool was adopted to assess the risk of bias in individual studies and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guideline was employed to assess confidence in the body of evidence.
RESULTS
A total 14 studies comprising four cohorts (13,155 cases among 372,802 exposed subjects), nine case-control and one case-referent studies of female subjects (39,462 cases and 20,739 controls) across seven countries and published between 2001 and 20 were included for review. Participants in the highest LAN exposure category were associated with higher risk of breast cancer in reference to those in the lowest (SRR: 1.12; 95% CI: 1.06-1.18; I = 39% for outdoor LAN, and SRR: 1.13; 95%CI: 1.05-1.21; I = 19% for indoor LAN). Pooled evidence identified relatively pronounced association of outdoor LAN exposure and breast cancer among women with estrogen receptor positive (ER+) tumor (SRR: 1.21; 95% CI: 1.04-1.40) and premenopausal status (SRR: 1.21; 95% CI: 1.06-1.37). The final rate of confidence in the body of evidence generated was graded as 'moderate' based on GRADE guideline.
DISCUSSION
LAN exposure was consistently associated with higher breast cancer risk corroborating NTP's recommendations which anticipates excessive LAN as human carcinogen.
Topics: Breast Neoplasms; Case-Control Studies; Female; Humans; Light; Risk Assessment
PubMed: 33131852
DOI: 10.1016/j.scitotenv.2020.143159 -
American Journal of Obstetrics and... Feb 2022There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying...
There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.
Topics: Antibodies, Monoclonal; Antioxidants; Antithrombin III; Biological Products; Blood Component Removal; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Metformin; Micronutrients; Placenta Growth Factor; Plant Extracts; Pravastatin; Pre-Eclampsia; Pregnancy; Proton Pump Inhibitors; RNA, Small Interfering; Recombinant Proteins; Sulfasalazine; Vascular Endothelial Growth Factor Receptor-1
PubMed: 32946849
DOI: 10.1016/j.ajog.2020.09.014 -
Pharmacological Research Nov 2020Restoring the lost physiological functions of the substantia nigra in Parkinson's disease (PD) is an important goal of PD therapy. The present article reviews a) novel...
Restoring the lost physiological functions of the substantia nigra in Parkinson's disease (PD) is an important goal of PD therapy. The present article reviews a) novel drug targets that should be targeted to slow PD progression, and b) clinical and experimental research data reporting new treatments targeting immune-inflammatory and oxidative pathways. A systematic search was performed based on the major databases, i.e., ScienceDirect, Web of Science, PubMed, CABI Direct databases, and Scopus, on relevant studies performed from 1900 to 2020. This review considers the crucial roles of mitochondria and immune-inflammatory and oxidative pathways in the pathophysiology of PD. High levels of oxidative stress in the substantia nigra, as well as modifications in glutathione regulation, contribute to mitochondrial dysfunction, with a decline in complex I of the mitochondrial electron transport chain reported in PD patients. Many papers suggest that targeting antioxidative systems is a crucial aspect of preventive and protective therapies, even justifying the utilization of N-acetylcysteine (NAC) supplementation to fortify the protection afforded by intracellular glutathione. Dietary recommended panels including ketogenetic diet, muscular exercise, nutraceutical supplementation including NAC, glutathione, nicotine, caffeine, melatonin, niacin, and butyrate, besides to nonsteroidal anti-inflammatory drugs (NSAIDs), and memantine treatment are important aspects of PD therapy. The integration of neuro-immune, antioxidant, and nutritional approaches to treatment should afford better neuroprotection, including by attenuating neuroinflammation, nitro-oxidative stress, mitochondrial dysfunction, and neurodegenerative processes. Future research should clarify the efficacy, and interactions, of nicotine receptor agonists, gut microbiome-derived butyrate, melatonin, and NSAIDs in the treatment of PD.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Antiparkinson Agents; Dietary Supplements; Disease Progression; Humans; Inflammation Mediators; Nutritional Status; Oxidative Stress; Parkinson Disease; Substantia Nigra
PubMed: 32652199
DOI: 10.1016/j.phrs.2020.105065 -
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