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1.
Anesth Analg ; 132(4): e50-e55, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33560660

RESUMO

Many general anesthetics potentiate gamma-aminobutyric acid (GABA) A receptors but their neuroanatomic sites of action are less clear. GABAergic neurons in the rostromedial tegmental nucleus (RMTg) send inhibitory projections to multiple arousal-promoting nuclei, but the role of these neurons in modulating consciousness is unknown. In this study, designer receptors exclusively activated by designer drugs (DREADDs) were targeted to RMTg GABAergic neurons of Vgat-ires-Cre mice. DREADDs expression was found in the RMTg and other brainstem regions. Activation of these neurons decreased movement and exploratory behavior, impaired motor coordination, induced electroencephalogram (EEG) oscillations resembling nonrapid eye movement (NREM) sleep without loss of righting and reduced the dose requirement for sevoflurane-induced unconsciousness. These results suggest that GABAergic neurons in the RMTg and other brainstem regions promote sedation and facilitate sevoflurane-induced unconsciousness.


Assuntos
Anestésicos Inalatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Tronco Encefálico/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Neurônios GABAérgicos/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Sevoflurano/farmacologia , Sono/efeitos dos fármacos , Animais , Tronco Encefálico/metabolismo , Ondas Encefálicas/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Feminino , Neurônios GABAérgicos/metabolismo , Masculino , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos
2.
Yakugaku Zasshi ; 141(1): 93-110, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33390452

RESUMO

There has been little information about the role of histamine on the central nervous system (CNS), different from dopamine and serotonin. In the present study, therefore, the effects of histamine and related compounds on the CNS were studied using rats. Intracerebroventricular (i.c.v.) injection of histamine and 2-methylhistamine ameliorated memory deficit after long interrution of learning in active avoidance response. First generation H1-antagonists inhibited active avoidance response, whereas newly develpoed H1-antagonists showed little effect. α-Fluoromethylhistidine, an histidine decarboxylase inhibitor, also inhibited active avoidance response. In radial maze performance, almost the same findings were obtained. I.c.v. injection of histamine and H1-agonists inhibited amygdaloid kindled seizures. First generation H1-antagonists attenuated histamine-induced inhibition of amygdaloid kindled seizures. Both i.c.v. and intraperitoneal injections of H3-antagonist, thioperamide, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of thioperamide was inhibited by an H3-agonists and H1-antagonists. Similar to nitrazepam, diphenhydramine and chlorpheniramine caused a shortening of sleep latency. On the other hand, no significant effects were observed with second generation H1-antagonists. These findings suggest that histamine plays an important role in learning and memory via H1-receptors, an inhibition of amygdaloid kindled seizures induced by histamine occurred through not only H1-receptors but also H3-receptors, and that classic H1-antagonists can be useful as a effective hypnotic for difficulty in falling asleep.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Histamina/farmacologia , Metilistaminas/farmacologia , Metilistidinas/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Histamina/administração & dosagem , Histamina/metabolismo , Histamina/fisiologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Hipnóticos e Sedativos , Injeções Intraventriculares , Excitação Neurológica/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Metilistaminas/administração & dosagem , Metilistidinas/administração & dosagem , Camundongos , Ratos , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/fisiologia , Convulsões/tratamento farmacológico , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
3.
Ecotoxicol Environ Saf ; 211: 111932, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33476852

RESUMO

Evidence from numerous epidemiological studies for the relationship between mental disorder and sleep quality was inconclusive and few studies assessed the modification effect of exposure to ambient air PM1 (particulate matter with an aerodynamic diameter ≤ 1.0 µm) on this association. In this study, 27,572 participants aged 18-79 years from The Henan Rural Cohort study were included in the final analyses. The Patient Health Questionnaire-2 (PHQ-2) and Generalized Anxiety Disorder-2 (GAD-2) scales were used to estimate the frequency of depression and anxiety symptoms of all participants, respectively. The Pittsburgh Sleep Quality Index (PSQI) scale was used to assess night sleep quality and PSQI global score (GSC) ≥ 6 was classified as poor sleep quality. The three-year average exposure concentration of PM1 before the baseline survey was determined as long-term exposure concentration of ambient PM1. Logistic regression model was conducted to estimate the independent or joint effect of depression/anxiety symptoms and ambient PM1 exposure on poor sleep quality. In the adjusted models, the odds ratios (ORs) and 95% confidence intervals (95% CIs) of poor sleep quality associated with depression and anxiety symptoms were 3.75 (3.37, 4.17) and 3.42 (3.06, 3.81), respectively, and that associated with long-term exposure to PM1 was 1.06 (1.03, 1.09). An interaction effect was observed between anxiety symptoms score and PM1 concentration on poor sleep quality. With the increment of PM1 concentration, the association was strengthened between depression/anxiety symptoms and poor sleep quality. Besides, compared with the reference group, the ORs (95% CIs) of poor sleep quality in those with comorbidity of depression and anxiety symptoms were 4.98 (3.95, 6.29), 5.23 (3.98, 6.87), 5.76 (4.42, 7.49), and 5.58 (3.83, 8.14), respectively, from the first to the fourth quartile level of the PM1 concentration. These findings suggested that long-term exposure to PM1 strengthened the association of depression/anxiety symptoms with poor sleep quality in rural China.


Assuntos
Poluição do Ar/estatística & dados numéricos , Exposição Ambiental/estatística & dados numéricos , Material Particulado/toxicidade , Sono/efeitos dos fármacos , Adolescente , Adulto , Idoso , Ansiedade , China , Estudos de Coortes , Depressão , Feminino , Humanos , Modelos Logísticos , Masculino , Transtornos Mentais , Pessoa de Meia-Idade , Razão de Chances , Material Particulado/análise , População Rural , Adulto Jovem
4.
Sr Care Pharm ; 36(2): 83-91, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33509331

RESUMO

OBJECTIVE: The purpose of this systematic review is to evaluate the available evidence for safety and efficacy of over-the-counter (OTC) sleep aids used for the treatment of insomnia in older people.
DATA SOURCES: PubMed, EBSCO, and International Pharmaceutical Abstracts.
STUDY SELECTION: Five studies were included that involved humans 65 years of age and older being evaluated on OTC sleep aids in the outpatient setting.
DATA EXTRACTION: Data extraction from each study included primary and secondary efficacy endpoints, such as differences in the mean total sleep time, sleep latency, sleep efficiency, and number of awakenings, along with safety endpoints, such as psychomotor ability, cognitive ability, and adverse effect profiles. Both subjective and objective measures of changes in sleep and adverse effects were included.
DATA SYNTHESIS: Diphenhydramine had a statistically significant increase in sedation and decrease in number of awakenings but was not shown to be any less or more safe than compared products. Despite lacking safety issues, valerian was found to have no effect on subjective or objective sleep outcomes. Overall, melatonin had the most evidence and was found to have a statistically significant positive impact on sleep measures without safety issues.
CONCLUSION: Diphenhydramine and melatonin appear to be efficacious in improving some sleep measures while causing minimal adverse effects. However, there are very few studies that examine the use of over-the-counter sleep aids in those 65 years of age and older with primary insomnia. Additional studies are needed in this population.


Assuntos
Difenidramina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Melatonina/administração & dosagem , Medicamentos sem Prescrição , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Sono/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Difenidramina/efeitos adversos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Melatonina/efeitos adversos , Valeriana
5.
J Ethnopharmacol ; 264: 113276, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32818573

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ashwagandha (Withania somnifera (L.) Dunal.) is long known for its sleep-inducing effects. Ashwagandha can be proposed as an alternative to the recommended present treatments for insomnia. This study aimed to evaluate the pharmacological effect of Ashwagandha root extract on sleep in healthy subjects and also in the subjects having insomnia. MATERIAL AND METHODS: We performed a randomized, parallel-group, stratified design, placebo-controlled study. A total of 80 eligible participants, 40 in Arm-A (healthy) and 40 in Arm-B (insomnia) were assigned to two groups, either Ashwagandha or placebo and studied for 8-weeks. The assessment was done based on the sleep parameters (Sleep Onset Latency, Total Sleep Time, Wake After Sleep Onset, Total time in bed, and Sleep Efficiency), Pittsburgh Sleep Quality Index and Hamilton Anxiety scale-A questionnaire, mental alertness on rising assessment, and sleep quality questionnaire. Safety and adverse events along with the concomitant medication were also assessed. RESULTS: In both healthy and insomnia subjects, there was a significant improvement in the sleep parameters in the Ashwagandha root extract supplemented group. The improvement was found more significant in insomnia subjects than healthy subjects. Repeat measure Analysis of variance (ANOVA) confirmed the significant improvement in SOL (p 0.013), HAM-A outcomes (p < 0.05), mental alertness (p 0.01), and sleep quality (p < 0.05) of the insomnia patients. A two-way ANOVA was used to confirm the outcomes that denoted sleep onset latency (p < 0.0001) and sleep efficiency (p < 0.0001) as the most improved parameters, followed by TST (p < 0.002) and WASO(p < 0.040). All these parameters (SOL, TST, WASO, TIB, SE, PSQI, HAM-A, Mental Alertness, and Sleep quality) were also statistically assessed for the significant improvement within the group both for the treatment, and the placebo groups in the healthy and the insomnia datasets. Obtained results suggest statistically significant (p < 0.0001) changes between the baseline values and the end of the study results except for the HAM-A and the mental alertness scoresn the healthy subject group. CONCLUSION: The present study confirms that Ashwagandha root extract can improve sleep quality and can help in managing insomnia. Ashwagandha root extract was well tolerated by all the participants irrespective of their health condition and age. Additional clinical trials are required to generalize the outcome.


Assuntos
Extratos Vegetais/uso terapêutico , Raízes de Plantas , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Actigrafia/métodos , Adulto , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/fisiopatologia
6.
J Ethnopharmacol ; 265: 113316, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32866569

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Calea zacatechichi is a plant with an extensive popular and ritual use in Mexico. In healthy volunteers, it induces well-being and tranquility senses, and facilitates superficial stages of sleep. However, anxiolytic, and antidepressant-like effects and changes on the sleep-waking stages have not been explored. AIM: To determine anxiolytic and antidepressant-like effects of an aqueous extract of C. zacatechichi (CZ) in rodents and to analyze their effects on hippocampal activity in the rat sleep-waking cycle. MATERIAL AND METHODS: CZ anxiolytic- and antidepressant-like effects were evaluated in several mice and rat behavioral paradigms. CZ effects on temporal distribution of sleep were described, and hippocampus EEG frequency patterns were analyzed during the sleep-waking cycle; absolute and relative powers were analyzed during Rapid Eye Movements (REM) and non-REM sleep stages. CZ chemical analysis was performed by UPLC-ESI-MS. RESULTS: CZ produced specific and robust anxiolytic- and antidepressant-like effects in mice and rats, similar to those of prototypical drugs, at doses ranging from 0.5 to 50 mg/kg. CZ at 100 mg/kg produced visible mild sedative effects in rats, associated with a significant increase in Slow Wave Sleep episodes during a 6 h recording, and enhanced fast frequencies of hippocampus (gamma-band:31-50 Hz) during REM sleep. CONCLUSION: Results could support the well-being and tranquility senses reported by healthy consumers, and to explain the oneiric content during dreams and some improvements in cognitive processes described by consumers. Anxiolytic- and antidepressant-like effects of this species, reported for first time in this study could improve some aspects of mental health.


Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Asteraceae/química , Extratos Vegetais/farmacologia , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/isolamento & purificação , Antidepressivos/administração & dosagem , Antidepressivos/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , México , Camundongos , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Sono/efeitos dos fármacos , Sono REM/efeitos dos fármacos
7.
PLoS One ; 15(9): e0238723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32916693

RESUMO

The aim of this study was to examine the risk of falls associated with the use of non-gamma amino butyric acid (GABA) sleep medications, suvorexant and ramelteon. This case-control and case-crossover study was performed at the Kudanzaka Hospital, Chiyoda Ward, Tokyo. A total of 325 patients who had falls and 1295 controls matched by sex and age were included. The inclusion criteria for the case group were hospitalized patients who had their first fall and that for the control were patients who were hospitalized and did not have a fall, between January 2016 and November 2018. The internal sleep medications administered were classified as suvorexant, ramelteon, non-benzodiazepines, benzodiazepines, or kampo. In the case-control study, age, sex, clinical department, the fall down risk score, and hospitalized duration were adjusted in the logistic regression model. In the case-control study, multivariable logistic regression showed that the use of suvorexant (odds ratio [OR]: 2.61, 95% confidence interval [CI]: 1.29-5.28), nonbenzodiazepines (OR: 2.49, 95% CI: 1.73-3.59), and benzodiazepines (OR: 1.65, 95% CI: 1.16-2.34) was significantly associated with an increased OR of falls. However, the use of ramelteon (OR: 1.40, 95% CI: 0.60-3.16) and kampo (OR: 1.55, 95% CI: 0.75-3.19) was not significantly associated with an increased OR of falls. In the case-crossover study, the use of suvorexant (OR: 1.78, 95% CI: 1.05-3.00) and nonbenzodiazepines (OR: 1.63, 95% CI: 1.17-2.27) was significantly associated with an increased OR of falls. Similar patterns were observed in several sensitivity analyses. It was suggested that suvorexant increases the OR of falls. This result is robust in various analyses. This study showed that the risk of falls also exists for non-GABA sleep medication, suvorexant, and thus it is necessary to carefully prescribe hypnotic drugs under appropriate assessment.


Assuntos
Acidentes por Quedas , Azepinas/efeitos adversos , Indenos/efeitos adversos , Medicamentos Indutores do Sono/efeitos adversos , Triazóis/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Azepinas/administração & dosagem , Benzodiazepinas/administração & dosagem , Benzodiazepinas/efeitos adversos , Estudos Cross-Over , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Indenos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sono/efeitos dos fármacos , Sono/fisiologia , Triazóis/administração & dosagem
8.
Proc Natl Acad Sci U S A ; 117(40): 25128-25137, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958651

RESUMO

Melatonin (Mel) promotes sleep through G protein-coupled receptors. However, the downstream molecular target(s) is unknown. We identified the Caenorhabditis elegans BK channel SLO-1 as a molecular target of the Mel receptor PCDR-1-. Knockout of pcdr-1, slo-1, or homt-1 (a gene required for Mel synthesis) causes substantially increased neurotransmitter release and shortened sleep duration, and these effects are nonadditive in double knockouts. Exogenous Mel inhibits neurotransmitter release and promotes sleep in wild-type (WT) but not pcdr-1 and slo-1 mutants. In a heterologous expression system, Mel activates the human BK channel (hSlo1) in a membrane-delimited manner in the presence of the Mel receptor MT1 but not MT2 A peptide acting to release free Gßγ also activates hSlo1 in a MT1-dependent and membrane-delimited manner, whereas a Gßλ inhibitor abolishes the stimulating effect of Mel. Our results suggest that Mel promotes sleep by activating the BK channel through a specific Mel receptor and Gßλ.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Melatonina/farmacologia , Sono/genética , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Técnicas de Inativação de Genes , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Melatonina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptor MT2 de Melatonina/genética , Sono/efeitos dos fármacos , Transmissão Sináptica/genética
9.
PLoS One ; 15(7): e0236318, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726319

RESUMO

Lately, Drosophila has been favored as a model in sleep and circadian rhythm research due to its conserved mechanism and easily manageable operation. These studies have revealed the sophisticated parameters in whole-day sleep profiles of Drosophila, drawing connections between Drosophila sleep and human sleep. In this study, we tested several sleep deprivation protocols (mechanical shakes and light interruptions) on Drosophila and delineated their influences on Drosophila sleep. We applied a daytime light-deprivation protocol (DD) mimicking jet-lag to screen drugs that alleviate sleep deprivation. Characteristically, classical sleep-aid compounds exhibited different forms of influence: phenobarbital and pentobarbital modified total sleep time, while melatonin only shortened the latency to sleep. Such results construct the basis for further research on sleep benefits in other treatments in Drosophila. We screened seven herb extracts, and found very diverse results regarding their effect on sleep regulation. For instance, Panax notoginseng and Withania somnifera extracts displayed potent influence on total sleep time, while Melissa officinalis increased the number of sleep episodes. By comparing these treatments, we were able to rank drug potency in different aspects of sleep regulation. Notably, we also confirmed the presence of sleep difficulties in a Drosophila Alzheimer's disease (AD) model with an overexpression of human Abeta, and recognized clear differences between the portfolios of drug screening effects in AD flies and in the control group. Overall, potential drug candidates and receipts for sleep problems can be identified separately for normal and AD Drosophila populations, outlining Drosophila's potential in drug screening tests in other populations if combined with the use of other genetic disease tools.


Assuntos
Extratos Vegetais/farmacologia , Privação do Sono/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Sono/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Animais , Ritmo Circadiano/efeitos dos fármacos , Modelos Animais de Doenças , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica/genética , Humanos , Melatonina/farmacologia , Mutação , Panax notoginseng/química , Fenobarbital/farmacologia , Extratos Vegetais/química , Sono/efeitos dos fármacos , Sono/genética , Privação do Sono/genética , Privação do Sono/fisiopatologia , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Withania/química
10.
Health Qual Life Outcomes ; 18(1): 212, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631438

RESUMO

BACKGROUND: Insomnia continues to be neglected globally, despite its high prevalence. Guidelines by the health regulatory agencies call for studies to evaluate the effect of sedative-hypnotics on sleep quality. METHODS: We conducted a pre-post observational study to evaluate sleep quality among 186 inpatients receiving short-term oral sedative-hypnotic therapy in a tertiary care teaching hospital in Kozhikode (Kerala), India. Using Pittsburgh Sleep Quality Index_Past-Week (PSQI_PW) questionnaire, patients were interviewed upon hospital admission and at follow up after ≥1-week of sedative-hypnotic therapy. Additionally, we interviewed 36 physicians to understand the current clinical perception about sedative-hypnotics. RESULTS: Mean (SD) age of the study patients was 59 (7.5) years. Majority (63.4%) of the patients were men. Of the various primary diagnoses for hospitalization, cardiovascular disease was the most common (22.6%, n = 49). Sedative-hypnotic therapy improved the mean (SD) PSQI_PW overall score by 6.79 points (pre: 12.70 (3.5) vs. post: 5.91 (2.8); p < 0.0001). Statistically significant improvements in sleep duration, latency, efficacy, and day dysfunction were observed. Higher proportion of study patients were prescribed benzodiazepines (73.7%) compared to zolpidem (26.3%). Patients treated with zolpidem reported higher improvements in mean overall PSQI_PW scores compared to those treated with benzodiazepines, however these differences were not statistically significant upon adjusting for age, gender and primary diagnosis for hospitalization. Qualitative interviews indicate that that physicians consider zolpidem to be safer and more efficacious. CONCLUSIONS: In our study, sedative-hypnotic therapy helped improve sleep quality among the hospitalized patients. More studies evaluating the comparative efficacy and safety of zolpidem vs. benzodiazepines - including among patient groups with varying demographic and clinical characteristics - are needed. India must develop evidence-based treatment guidelines to inform the clinical practice around the use of sedative-hypnotics.


Assuntos
Benzodiazepinas/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Pacientes Internados/estatística & dados numéricos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Zolpidem/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
11.
Am J Respir Cell Mol Biol ; 63(4): 502-509, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32603263

RESUMO

Respiratory depression is the main cause of morbidity and mortality associated with opioids. Obesity increases opioid-related mortality, which is mostly related to comorbid obstructive sleep apnea. Naloxone, a µ-opioid receptor blocker, is an effective antidote, but it reverses analgesia. Like humans with obesity, mice with diet-induced obesity hypoventilate during sleep and develop obstructive sleep apnea, which can be treated with intranasal leptin. We hypothesized that intranasal leptin reverses opioid-induced sleep-disordered breathing in obese mice without decreasing analgesia. To test this hypothesis, mice with diet-induced obesity were treated with morphine at 10 mg/kg subcutaneously and with leptin or placebo intranasally. Sleep and breathing were recorded by barometric plethysmography, and pain sensitivity was measured by the tail-flick test. Excitatory postsynaptic currents were recorded in vitro from hypoglossal motor neurons after the application of the µ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin and leptin. Morphine dramatically increased the frequency of apneas and greatly increased the severity of hypoventilation and obstructive sleep apnea. Leptin decreased the frequency of apneas, improved obstructive sleep apnea, and completely reversed hypoventilation, whereas morphine analgesia was enhanced. Our in vitro studies demonstrated that [D-Ala2, N-MePhe4, Gly-ol]-enkephalin reduced the frequency of excitatory postsynaptic currents in hypoglossal motoneurons and that application of leptin restored excitatory synaptic neurotransmission. Our findings suggest that intranasal leptin may prevent opioid respiratory depression during sleep in patients with obesity receiving opioids without reducing analgesia.


Assuntos
Analgésicos Opioides/efeitos adversos , Leptina/administração & dosagem , Respiração/efeitos dos fármacos , Síndromes da Apneia do Sono/induzido quimicamente , Síndromes da Apneia do Sono/prevenção & controle , Sono/efeitos dos fármacos , Administração Intranasal/métodos , Analgesia/métodos , Animais , Modelos Animais de Doenças , Encefalinas/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Morfina/farmacologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Receptores Opioides mu/metabolismo , Síndromes da Apneia do Sono/metabolismo , Transmissão Sináptica/efeitos dos fármacos
12.
J Laryngol Otol ; 134(5): 447-452, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32493527

RESUMO

OBJECTIVES: This paper aimed to: retrospectively analyse single-centre results in terms of surgical success, respiratory outcomes and adverse events after short-term follow up in obstructive sleep apnoea patients treated with upper airway stimulation; and evaluate the correlation between pre-operative drug-induced sleep endoscopy findings and surgical success. METHODS: A retrospective descriptive cohort study was conducted, including a consecutive series of obstructive sleep apnoea patients undergoing implantation of an upper airway stimulation system. RESULTS: Forty-four patients were included. The total median Apnoea-Hypopnea Index and oxygen desaturation index significantly decreased from 37.6 to 8.3 events per hour (p < 0.001) and from 37.1 to 15.9 events per hour (p < 0.001), respectively. The surgical success rate was 88.6 per cent, and did not significantly differ between patients with or without complete collapse at the retropalatal level (p = 0.784). The most common therapy-related adverse event reported was (temporary) stimulation-related discomfort. CONCLUSION: Upper airway stimulation is an effective and safe treatment in obstructive sleep apnoea patients with continuous positive airway pressure intolerance or failure. There was no significant difference in surgical outcome between patients with tongue base collapse with or without complete anteroposterior collapse at the level of the palate.


Assuntos
Terapia por Estimulação Elétrica/métodos , Apneia Obstrutiva do Sono/terapia , Pressão Positiva Contínua nas Vias Aéreas , Terapia por Estimulação Elétrica/efeitos adversos , Endoscopia/métodos , Feminino , Humanos , Nervo Hipoglosso , Masculino , Pessoa de Meia-Idade , Polissonografia , Cuidados Pós-Operatórios , Cuidados Pré-Operatórios , Estudos Retrospectivos , Sono/efeitos dos fármacos , Decúbito Dorsal , Resultado do Tratamento
13.
JAMA Netw Open ; 3(6): e206614, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32484552

RESUMO

Importance: Many shift workers have difficulty sleeping during the daytime owing to an inappropriately timed circadian drive for wakefulness. Objective: To determine whether a dual hypocretin receptor antagonist would enable shift workers to have more daytime sleep. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial included 2 weeks of baseline data and 3 weeks of intervention data, from March 2016 to December 2018. Individuals were recruited through poster advertisements in the broader San Francisco Bay area in California. From an initial voluntary recruitment cohort of 38 shift workers, 19 individuals with self-reported difficulty sleeping during the daytime following night work shift were included. Data were analyzed from Janaury to March 2019. Interventions: 1 week of 10 mg suvorexant or placebo, titrated upward to 20 mg suvorexant or placebo for 2 additional weeks. Main Outcomes and Measures: Objective (ie, actigraphy) and subjective (ie, sleep logs) measures of sleep. Results: Among 19 participants who completed the study (mean [SD] age, 37.7 [11.1] years; 13 [68%] men), 8 participants (42%) were assigned to the suvorexant group and 11 participants (58%) were assigned to the placebo group. Compared with individuals in the placebo group, individuals in the suvorexant group increased their objective total sleep time by a mean (SE) of 1.04 (0.53) hours (P = .05) at the end of 1 week of 10-mg doses and by 2.16 (0.75) hours (P = .004) by the end of the 2 weeks of 20-mg doses. Subjective sleep was similarly improved as, compared with the placebo group, individuals in the suvorexant group increased their subjective total sleep time by a mean (SE) of 2.08 (0.47) hours (P < .001) at the end of 1 week of 10-mg doses and by 2.97 (0.56) hours (P < .001) by the end of the 2 weeks of 20-mg doses. Physician ratings of daytime sleep aligned with these measures, as there was no change in the placebo group and a much improved change in the suvorexant group. No adverse events were reported in the suvorexant group. Conclusions and Relevance: This pilot study found that the use of a dual hypocretin receptor antagonist in shift workers under real-world conditions resulted in more than 2 extra hours of daytime sleep per episode. Future research should confirm this pilot finding in a larger sample size and examine whether, over the long term, use of this medication has a concomitant improvement in medical and psychiatric health as well as workplace performance and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02491788.


Assuntos
Azepinas/uso terapêutico , Antagonistas dos Receptores de Orexina/uso terapêutico , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Sono/efeitos dos fármacos , Triazóis/uso terapêutico , Actigrafia/métodos , Adulto , California/epidemiologia , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Transtornos do Sono do Ritmo Circadiano/epidemiologia , Transtornos do Sono do Ritmo Circadiano/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/fisiopatologia
14.
Psychopharmacology (Berl) ; 237(8): 2517-2530, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445053

RESUMO

RATIONALE: Major depression is a serious, but common, psychological disorder, which consists of a long-lasting depressive mood, feelings of helplessness, anhedonia, and sleep disturbances. It has been reported that rats with bilateral olfactory bulbectomies (OBXs) exhibit depressive-like behaviors which indicates that the olfactory bulb (OB) plays an important role in the formation of depression. However, which type of OB neurons plays an important role in the formation of depression remains unclear. OBJECTIVE: To determine the role of OB neuronal types in depression and related sleep-wake dysfunction. METHODS: Firstly, we established and evaluated a conventional physical bilateral OBX depression model. Secondly, we used chemical methods to ablate OB neurons, while maintaining the original shape, and evaluated depressive-like behaviors. Thirdly, we utilized AAV-flex-taCasp3-TEVp and transgenetic mice to specifically ablate the OB GABAergic or glutamatergic neurons, then evaluated depressive-like behaviors. RESULTS: Compared with measured parameters in sham mice, mice with OBXs or ibotenic acid-induced OB lesions exhibited depressive-like behaviors and sleep disturbances, as demonstrated by results of depressive-like behavior tests and sleep recordings. Selective lesioning of OB glutamatergic neurons, but not GABAergic neurons induced depressive-like behaviors and increased rapid eye movement sleep during the light phase of the circadian cycle. CONCLUSIONS: These results indicate that OB glutamatergic neurons play a key role in olfactory-related depression and sleep disturbance.


Assuntos
Depressão/metabolismo , Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Bulbo Olfatório/metabolismo , Bulbo Olfatório/cirurgia , Transtornos do Sono-Vigília/metabolismo , Técnicas de Ablação/métodos , Animais , Depressão/induzido quimicamente , Depressão/psicologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Ibotênico/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Distribuição Aleatória , Sono/efeitos dos fármacos , Sono/fisiologia , Transtornos do Sono-Vigília/induzido quimicamente
15.
Sleep Med Clin ; 15(2): 133-145, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32386689

RESUMO

The scope of this article is to review the effects on sleep of prescription drugs that are commonly prescribed for chronic insomnia in adults. The following groups are discussed: benzodiazepines and its receptor agonists, the dual orexin receptor antagonist suvorexant, melatonin and its receptor agonists, sedating antidepressants, and antipsychotics. Together with the neurobiologic and pharmacologic properties of these drugs, clinical effects are described, including subjective and objective effects on sleep duration, continuity, and architecture. Medical prescription information is given when available. Recently published American and European guidelines for the treatment of insomnia serve as reference frame.


Assuntos
Benzodiazepinas/uso terapêutico , Melatonina/uso terapêutico , Medicamentos Indutores do Sono/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Azepinas/farmacologia , Azepinas/uso terapêutico , Benzodiazepinas/farmacologia , Humanos , Melatonina/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/uso terapêutico , Medicamentos sob Prescrição/farmacologia , Medicamentos sob Prescrição/uso terapêutico , Medicamentos Indutores do Sono/farmacologia , Triazóis/farmacologia , Triazóis/uso terapêutico
16.
Sleep Med Clin ; 15(2): 301-310, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32386703

RESUMO

This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Hipnóticos e Sedativos/uso terapêutico , Melatonina/uso terapêutico , Transtornos do Sono do Ritmo Circadiano/tratamento farmacológico , Sono/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/farmacologia , Melatonina/farmacologia , Resultado do Tratamento
18.
PLoS One ; 15(4): e0231379, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302347

RESUMO

This randomized, double-blinded, placebo-controlled trial tested the hypothesis that 20mg of melatonin before and during the first cycle of adjuvant chemotherapy for breast cancer (ACBC) reduced the side effects associated with cognitive impairment. We evaluated the effects of melatonin on cognition, depressive symptoms and sleep quality, and whether these effects were related to serum levels of Brain Derived Neurotrophic Factor (BDNF) and its receptor, tropomyosin kinase B (TrkB). Thirty-six women were randomly assigned to receive melatonin or placebo for 10 days. To evaluate cognitive performance, we used the Trail-Making-Test Parts A and B (A-B), Rey Auditory-Verbal Learning Test (RAVLT), Controlled Oral Word Association Test (COWAT) and an inhibitory task type Go / No-Go. Our results revealed that melatonin improved executive function on TMT scores, enhanced episodic memory (immediate and delayed) and recognition on RAVLT, and increased verbal fluency in the orthographic COWAT. The TMT-A-B(A-B) were negatively correlated with baseline levels of TrkB and BDNF, respectively. At the end of treatment, changes in TrkB and BDNF were inversely associated with depressive symptoms and sleep quality, but not with the TMT scores. These results suggest a neuroprotective effect of melatonin to counteract the adverse effects of ACBC on cognitive function, sleep quality and depressive symptoms.


Assuntos
Neoplasias da Mama/patologia , Disfunção Cognitiva/prevenção & controle , Depressão/tratamento farmacológico , Melatonina/uso terapêutico , Sono , Adulto , Idoso , Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Depressão/etiologia , Método Duplo-Cego , Feminino , Humanos , Melatonina/farmacologia , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Testes Neuropsicológicos , Efeito Placebo , Receptor trkB/sangue , Sono/efeitos dos fármacos , Resultado do Tratamento
19.
Anesth Analg ; 130(5): 1211-1221, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32287128

RESUMO

BACKGROUND: Brain monitors tracking quantitative brain activities from electroencephalogram (EEG) to predict hypnotic levels have been proposed as a labor-saving alternative to behavioral assessments. Expensive clinical trials are required to validate any newly developed processed EEG monitor for every drug and combinations of drugs due to drug-specific EEG patterns. There is a need for an alternative, efficient, and economical method. METHODS: Using deep learning algorithms, we developed a novel data-repurposing framework to predict hypnotic levels from sleep brain rhythms. We used an online large sleep data set (5723 clinical EEGs) for training the deep learning algorithm and a clinical trial hypnotic data set (30 EEGs) for testing during dexmedetomidine infusion. Model performance was evaluated using accuracy and the area under the receiver operator characteristic curve (AUC). RESULTS: The deep learning model (a combination of a convolutional neural network and long short-term memory units) trained on sleep EEG predicted deep hypnotic level with an accuracy (95% confidence interval [CI]) = 81 (79.2-88.3)%, AUC (95% CI) = 0.89 (0.82-0.94) using dexmedetomidine as a prototype drug. We also demonstrate that EEG patterns during dexmedetomidine-induced deep hypnotic level are homologous to nonrapid eye movement stage 3 EEG sleep. CONCLUSIONS: We propose a novel method to develop hypnotic level monitors using large sleep EEG data, deep learning, and a data-repurposing approach, and for optimizing such a system for monitoring any given individual. We provide a novel data-repurposing framework to predict hypnosis levels using sleep EEG, eliminating the need for new clinical trials to develop hypnosis level monitors.


Assuntos
Ondas Encefálicas/fisiologia , Encéfalo/fisiologia , Análise de Dados , Aprendizado Profundo , Sono/fisiologia , Adulto , Idoso , Encéfalo/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Dexmedetomidina/administração & dosagem , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sono/efeitos dos fármacos
20.
Artigo em Inglês | MEDLINE | ID: mdl-32224987

RESUMO

Anxiety, mood disturbance, eating and sleep disorders, and dissatisfaction with body image are prevalent disorders in women with fibromyalgia. The authors of this study aimed to determine the effects of tryptophan (TRY) and magnesium-enriched (MG) Mediterranean diet on psychological variables (trait anxiety, mood state, eating disorders, self-image perception) and sleep quality in women with fibromyalgia (n = 22; 49 ± 5 years old). In this randomized, controlled trial, the participants were randomly assigned to the experimental group and the placebo group. The intervention group received a Mediterranean diet enriched with high doses of TRY and MG (60 mg of TRY and 60 mg of MG), whereas the control group received the standard Mediterranean diet. Pittsburgh Sleep Quality Questionnaire, Body Shape Questionnaire, State-Trait Anxiety Inventory (STAI), Profile of Mood States (POMS-29) Questionnaire, Eating Attitudes Test-26, and Trait Anxiety Inventory were completed before and 16 weeks after the intervention. Significant differences were observed between groups after the intervention for the mean scores of trait anxiety (p = 0.001), self-image perception (p = 0.029), mood disturbance (p = 0.001), and eating disorders (p = 0.006). This study concludes that tryptophan and magnesium-enriched Mediterranean diet reduced anxiety symptoms, mood disturbance, eating disorders, and dissatisfaction with body image but did not improve sleep quality in women with fibromyalgia.


Assuntos
Ansiedade/tratamento farmacológico , Dieta Mediterrânea , Fibromialgia/psicologia , Magnésio/uso terapêutico , Sono/efeitos dos fármacos , Triptofano/uso terapêutico , Adulto , Feminino , Humanos , Pessoa de Meia-Idade
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