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1.
Postgrad Med ; 133(7): 772-783, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34292843

RESUMO

Excessive daytime sleepiness (EDS) affects approximately half of patients with obstructive sleep apnea (OSA) and can persist in some despite normalization of breathing, oxygenation, and sleep quality with primary OSA therapy, such as continuous positive airway pressure (CPAP). EDS is often overlooked and under discussed in the primary care setting and in the follow-up of CPAP-treated patients due to difficult assessment of such a multi-dimensional symptom. This review aims to provide suggestions for procedures that can be implemented into routine clinical practice to identify, evaluate, and manage EDS in patients treated for OSA, including how to appropriately use various self-report and objective assessments along the clinical pathway and options for pharmacotherapy. In addition, examples of when it is appropriate to refer a patient to a sleep specialist for evaluation are discussed.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Distúrbios do Sono por Sonolência Excessiva/etiologia , Apneia Obstrutiva do Sono/complicações , Promotores da Vigília/uso terapêutico , Fatores Etários , Índice de Massa Corporal , Comorbidade , Diagnóstico Diferencial , Distúrbios do Sono por Sonolência Excessiva/terapia , Comportamentos Relacionados com a Saúde , Humanos , Estilo de Vida , Fatores de Risco , Autorrelato , Apneia Obstrutiva do Sono/terapia , Promotores da Vigília/administração & dosagem , Promotores da Vigília/efeitos adversos
3.
Cochrane Database Syst Rev ; 5: CD012714, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34031871

RESUMO

BACKGROUND: Idiopathic hypersomnia is a disorder of excessive daytime sleepiness, often accompanied by long sleep times or pronounced difficulty in awakening, in the absence of a known cause. The optimal treatment strategy for idiopathic hypersomnia is currently unknown. OBJECTIVES: To assess the effects of medications for daytime sleepiness and related symptoms in individuals with idiopathic hypersomnia and, in particular, whether medications may: 1. reduce subjective measures of sleepiness; 2. reduce objective measures of sleepiness; 3. reduce symptoms of cognitive dysfunction; 4. improve quality of life; and 5. be associated with adverse events. SEARCH METHODS: We searched the following databases on 4 February 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 1 February 2021), and reference lists of articles. CRS Web includes randomized or quasi-randomized controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialized registers of Cochrane Review Groups, including the Cochrane Epilepsy Group. We previously searched the WHO ICTRP separately when loading of ICTRP records into CRS Web was temporarily suspended. SELECTION CRITERIA: Randomized studies comparing any medication to placebo, another medication, or a behavioral intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional data. We collected data on adverse events from the included trials. MAIN RESULTS: We included three trials, with a total of 112 participants. Risk of bias was low for the included studies. Two pharmaceutical company-sponsored trials compared modafinil with placebo, involving 102 participants, nearly all of whom had idiopathic hypersomnia without long sleep time. Modafinil significantly improved self-reported sleepiness on the Epworth Sleepiness Scale by 5.08 points more than placebo (95% confidence interval (CI) 3.01 to 7.16; 2 studies, 101 participants; high-certainty evidence). Modafinil also significantly improved disease severity on the Clinical Global Impression of Severity scale by 1.02 points (95% CI 0.11 to 1.93; 1 study, 30 participants; moderate-certainty evidence) and resulted in a greater proportion of participants who were "much improved" or "very much improved" on the Clinical Global Impression of Change (odds ratio (OR) for improvement 5.14, 95% CI 1.76 to 15.00; 1 study, 70 participants; moderate-certainty evidence). Ability to remain awake on the Maintenance of Wakefulness Test was significantly improved with modafinil, by 4.74 minutes more than with placebo (95% CI 2.46 to 7.01; 2 studies, 99 participants; high-certainty evidence). Ratings of exhaustion and effectiveness/performance were improved with modafinil compared to placebo in one study. Number of naps per week was no different between modafinil and placebo across two studies. Participants receiving modafinil experienced more side effects, although the difference did not reach statistical significance (OR 1.68, 95% CI 0.28 to 9.94; 2 studies, 102 participants; low-certainty evidence). One trial studying 20 participants with different disorders of sleepiness included 10 participants with idiopathic hypersomnia, with or without long sleep time, and compared clarithromycin to placebo. We only included the subset of trial data for those participants with idiopathic hypersomnia, per our protocol. There were no significant differences between clarithromycin and placebo for the Epworth Sleepiness Scale, psychomotor vigilance testing, sleep inertia, other subjective ratings, or side effects. AUTHORS' CONCLUSIONS: Modafinil is effective for the treatment of several aspects of idiopathic hypersomnia symptomatology, based on studies predominantly including participants with idiopathic hypersomnia without long sleep times, with low risk of bias, and evidence certainty ranging from high to low. There is insufficient evidence to conclude whether clarithromycin is effective for the treatment of idiopathic hypersomnia. There is a clear need for additional studies testing interventions for the treatment of idiopathic hypersomnia.


Assuntos
Claritromicina/uso terapêutico , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Hipersonia Idiopática/complicações , Modafinila/uso terapêutico , Promotores da Vigília/uso terapêutico , Viés , Distúrbios do Sono por Sonolência Excessiva/etiologia , Humanos , Placebos/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Vigília
4.
Pharmacol Biochem Behav ; 196: 172968, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32593791

RESUMO

BACKGROUND: Individual responses to the effects of inadequate sleep have been well documented; some people are more vulnerable to the effects of sleep loss than others. Fatigue-vulnerable individuals generally require access to effective fatigue countermeasures; however, the question arises as to whether these fatigue-vulnerable individuals receive the same benefits shown in group efficacy data. The present study administered modafinil to individuals to determine its differential effects on performance of best and worst performers during sleep deprivation. METHODS: A sample of 22 men, age 21-40 yrs., was tested on 2 separate occasions during which they were kept awake for 36 h. During one period they received 200 mg modafinil; during the other they received placebo. Participants were tested on a variety of tasks while rested and at 5-hr intervals across the continuous wakefulness period. Performance for each cognitive task and subjective measure of fatigue from the placebo period was used to group individuals into high (HP) or low performance (LP) groups to indicate fatigue vulnerability for each task. RESULTS: Results indicated that on the MTS task, the HP group performed the same throughout the testing period, regardless of whether they received modafinil or not. However, the LP group significantly improved after receiving modafinil compared to placebo. Performance on the PVT showed the HP group had a small decrease in the number of lapses after receiving modafinil compared to placebo, whereas the LP group had a large decrease in lapses after receiving modafinil compared to placebo. Performance on the RDM showed no difference between groups, regardless of drug condition. Groups did not differ after receiving modafinil on subjective fatigue measured by the POMS. CONCLUSIONS: Depending on the task, HP individuals did not benefit substantially when administered modafinil compared to placebo. However, the LP individuals improved after receiving modafinil compared to placebo.


Assuntos
Modafinila/farmacologia , Privação do Sono/fisiopatologia , Promotores da Vigília/farmacologia , Adulto , Método Duplo-Cego , Humanos , Masculino , Placebos , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Adulto Jovem
5.
J Prev Med Hyg ; 61(1): E60-E65, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32490270

RESUMO

Introduction: The financial crisis which started in Greece about 10 years ago has affected the income of citizens, their quality of life, as well as social and occupational relationships. Aim of the present study was to assess the attitudes towards working conditions and personal life and to explore quality of life, as well as disorders in physical condition, sleep, mood and their predictors, among doctors working or being trained in a tertiary hospital of NE Greece. Methods: Included were 133 medical students and doctors of all ranks (61.7% males) practicing medicine in a university tertiary hospital in Greece. All of them answered a 31-item questionnaire regarding their working conditions, and personal life, daytime activities and sleeping habits. Results: In general, the majority reported dissatisfaction with the work environment, the salary and they rated their quality of life worse than that of the general population. Weekly workload exceeded 60 hours for the majority. No difference between sexes was revealed, with the exception of use of energy drinks which was more prevalent in males (70.7% vs. 51%, p = 0.022). Comparison between ranks revealed that medical students performed better in everyday activities and socialization, although prevalence of reported fatigue was higher in them. Finally, it was demonstrated that surgeons used more frequently medication to achieve sleep promotion (80.4% vs. 36%, p < 0.001) and daily energy (78.4% vs. 44%, p < 0.001). Conclusions: An overall dissatisfaction regarding workload, salary and quality of life is recorded among doctors of a tertiary hospital in Greece, with different coping strategies among subgroups.


Assuntos
Atitude do Pessoal de Saúde , Recessão Econômica , Médicos , Qualidade de Vida , Salários e Benefícios , Estudantes de Medicina , Carga de Trabalho , Afeto , Fadiga , Feminino , Grécia , Humanos , Masculino , Sono , Medicamentos Indutores do Sono/uso terapêutico , Participação Social , Promotores da Vigília/uso terapêutico
6.
Neurotox Res ; 38(2): 498-507, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32367472

RESUMO

Psychostimulant drugs, such as modafinil and caffeine, induce transcriptional alterations through the dysregulation of epigenetic mechanisms. We have previously demonstrated that acute modafinil administration is accompanied by multiple changes in the expression of histone deacetylases (HDACs) within the mouse medial prefrontal cortex (mPFC). Herein, we compared alterations in class IIa HDACs in the mouse mPFC and dorsal striatum (DS) after a single exposure to each psychostimulant. We treated male C57BL/6 mice with modafinil (90 mg/kg, i.p.), caffeine (10 mg/kg, i.p.), or vehicle and evaluated locomotor activity. Following, we examined hdac4, hdac5, and hdac7 mRNA expression using qRT-PCR and HDAC7, pHDAC7, and pHDACs4/5/7 using Western blot. Last, we explored generalized effects in N2a cell line using modafinil (100 µM and 1 mM) or caffeine (80 µM and 800 µM). Our results indicate that modafinil had greater effects on locomotor activity compared with caffeine. qRT-PCR experiments revealed that modafinil decreased hdac5 and hdac7 mRNA expression in the DS, while caffeine had no effects. In the mPFC, modafinil increased hdac7 mRNA expression, with no effects observed for caffeine. Western blot revealed that within the DS, modafinil induced increases in HDAC7, pHDAC7, and pHDACs4/5/7 protein expression, while, in the mPFC, caffeine induced decreases in HDAC7, pHDAC7, and pHDACs4/5/7 protein levels. In vitro studies revealed that modafinil increased hdac4, hdac5, and hdac7 mRNA levels in N2a, while caffeine only increased hdac5 at a higher dose. These findings support the notion that modafinil and caffeine exert distinct regulation of class IIa HDAC family members and that these transcriptional and translational consequences are region-specific.


Assuntos
Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Histona Desacetilases/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Modafinila/farmacologia , Animais , Linhagem Celular , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Masculino , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Promotores da Vigília/farmacologia
7.
Aerosp Med Hum Perform ; 91(6): 518-524, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32408936

RESUMO

BACKGROUND: Fatigue is a well-known hazard in aviation. In military fighter communities, policies have evolved to allow for in-flight use of pharmacological vigilance aids to counteract the negative effects of fatigue. With limited objective evidence supporting the role of these medications in continuous flight operations, the present study seeks to evaluate whether use of modafinil is associated with pilot aircraft carrier landing performance.METHODS: A retrospective, observational study was completed following carrier-based flight operations in support of Operation Inherent Resolve. All graded landing passes were included in the analysis. Mixed-effect multivariate linear regression analysis was utilized for the primary outcome of landing signal officer grade of landing performance following combat sorties for events with reported in-flight use of modafinil.RESULTS: A total of 1122 sorties were flown by 79 different pilots with an average landing pass grade of 3.86. The primary outcome of modafinil use in-flight was not generally associated with landing performance. In a subset analysis of more senior ranked aviators, modafinil use appeared to offer a relative performance improvement back to baseline (+0.19). Secondary outcome analysis revealed landing performance was associated with advanced landing technologies (+0.25), sorties later in deployment (+0.05 per 30 d), total career carrier landings (+0.03 per 100 traps), and longer mission duration (-0.04 per hour).DISCUSSION: In the context of evidence supporting subjective benefits of vigilance aid use by aircrew, the results of this study provide ample objective support to the controlled use of modafinil in the operational environment.Schallhorn CS. Vigilance aid use and aircraft carrier landing performance in pilots of tactical aircraft. Aerosp Med Hum Perform. 2020; 91(6):518-524.


Assuntos
Medicina Aeroespacial , Fadiga/tratamento farmacológico , Medicina Militar , Pilotos/normas , Aeronaves , Fadiga/prevenção & controle , Humanos , Modafinila/uso terapêutico , Estudos Retrospectivos , Promotores da Vigília/uso terapêutico , Desempenho Profissional
8.
Psychiatr Pol ; 54(1): 21-33, 2020 Feb 29.
Artigo em Inglês, Polonês | MEDLINE | ID: mdl-32447354

RESUMO

Eugeroics are a relatively new class of wakefulness-promoting agents. Thegroup includes adrafinil, modafinil and armodafinil. Modafinil is the most widely used and the best studied agent. Indications for the use of modafinil include the treatment of narcolepsy, shift-work sleep disorders and excessive daytime sleepiness associated with obstructive sleep apnea. Many studies show the utility of modafinil and armodafinil in the treatment of depression - both in monotherapy andas potentiation therapy if needed. Modafinil has proven to be effective in the treatment of residual symptoms of unipolar and bipolar depression such as fatigue, excessive sleepiness and some cognitive impairment. Research on armodafinil points to its effectiveness mainly in augmentation therapy of depression in the course of bipolar disorder. There are also reports on the effectiveness of eugeroics in special cases - seasonal depression, atypical depression with hyperphagia, apathy in the course of depression or as an isolated symptom, cancer-related fatigue in patients receiving chemotherapy, fatigue and excessive sleepiness in neurological diseases. Eugeroics due to their high selectivity of action in the CNS have a low addictive potential compared with other stimulants. The risk of manic switch is comparable to placebo. In general, they are well-tolerated and safe. The purpose of this paper is to review the literature on the use of eugeroics in the treatment of affective disorders.


Assuntos
Antidepressivos/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Promotores da Vigília/uso terapêutico , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Medicina Baseada em Evidências , Feminino , Humanos , Masculino , Modafinila/uso terapêutico , Resultado do Tratamento
9.
Neurotherapeutics ; 17(3): 1075-1086, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32297185

RESUMO

Huntington's disease (HD) is characterised by progressive symptoms including cognitive deficits and sleep/wake disturbances reflected in an abnormal electroencephalography (EEG). Modafinil, a wake-promoting and cognitive-enhancing drug, has been considered as a treatment for HD. We used HD (R6/2) mice to investigate the potential for using modafinil to treat sleep-wake disturbance in HD. R6/2 mice show sleep-wake and EEG changes similar to those seen in HD patients, with increased rapid eye movement sleep (REMS), decreased wakefulness/increased non-REMS (NREMS), and pathological changes in EEG spectra, particularly an increase in gamma power. We recorded EEG from R6/2 and wild-type mice treated with modafinil acutely (with single doses between 25 and 100 mg/kg; at 12 and 16 weeks of age), or chronically (64 mg/kg modafinil/day from 6 to 15 weeks). Acutely, modafinil increased wakefulness in R6/2 mice and restored NREMS to wild-type levels at 12 weeks. It also suppressed the pathologically increased REMS. This was accompanied by decreased delta power, increased peak frequency of theta, and increased gamma power. At 16 weeks, acute modafinil also restored wakefulness and NREMS to wild-type levels. However, whilst REMS decreased, it did not return to normal levels. By contrast, in the chronic treatment group, modafinil-induced wakefulness was maintained at 15 weeks (after 9 weeks of treatment). Interestingly, chronic modafinil also caused widespread suppression of power across the EEG spectra, including a reduction in gamma that increases pathologically in R6/2 mice. The complex EEG effects of modafinil in R6/2 mice should provide a baseline for further studies to investigate the translatability of these result to clinical practice.


Assuntos
Eletroencefalografia/métodos , Doença de Huntington/tratamento farmacológico , Modafinila/administração & dosagem , Promotores da Vigília/administração & dosagem , Vigília/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Eletroencefalografia/efeitos dos fármacos , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fases do Sono/efeitos dos fármacos , Fases do Sono/fisiologia , Vigília/fisiologia
10.
Brain Behav Immun ; 88: 878-886, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32311496

RESUMO

Modafinil is a psychostimulant drug approved by the FDA primarily for the treatment of sleep disorders such as narcolepsy, excessive daytime sleepiness and sleep apnea. Several documented but not yet approved uses for modafinil have been described over the last 30 years, including alleviating fatigue in neurological and neurodegenerative disorders. Recent evidence has suggested that modafinil may have an immunomodulatory effect. Here, we review the different effects of modafinil treatment in animal models of brain inflammation and peripheral immune function. We conclude that there is unequivocal evidence of an anti-inflammatory effect of modafinil in experimental animal models of brain inflammation and neurodegenerative disorders, including systemic inflammation and methamphetamine-induced neuroinflammation, Parkinson's disease, brain ischemia, and multiple sclerosis. Modafinil acts on resident glial cells and infiltrating immune cells, negatively affecting both innate and adaptive immune responses in the brain. We also review the outcomes of modafinil treatment on peripheral immune function. The results of studies on this subject are still controversial and far from conclusive, but point to a new avenue of research in relation to peripheral inflammation. The data reviewed here raise the possibility of modafinil being used as adjuvant treatment for neurological disorders in which inflammation plays an important role.


Assuntos
Estimulantes do Sistema Nervoso Central , Preparações Farmacêuticas , Promotores da Vigília , Animais , Compostos Benzidrílicos/uso terapêutico , Imunidade , Modafinila , Promotores da Vigília/uso terapêutico
11.
Br J Sports Med ; 54(16): 960-968, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32303523

RESUMO

OBJECTIVES: We investigated the management of travel fatigue and jet lag in athlete populations by evaluating studies that have applied non-pharmacological interventions (exercise, sleep, light and nutrition), and pharmacological interventions (melatonin, sedatives, stimulants, melatonin analogues, glucocorticoids and antihistamines) following long-haul transmeridian travel-based, or laboratory-based circadian system phase-shifts. DESIGN: Systematic review Eligibility criteria Randomised controlled trials (RCTs), and non-RCTs including experimental studies and observational studies, exploring interventions to manage travel fatigue and jet lag involving actual travel-based or laboratory-based phase-shifts. Studies included participants who were athletes, except for interventions rendering no athlete studies, then the search was expanded to include studies on healthy populations. DATA SOURCES: Electronic searches in PubMed, MEDLINE, CINAHL, Google Scholar and SPORTDiscus from inception to March 2019. We assessed included articles for risk of bias, methodological quality, level of evidence and quality of evidence. RESULTS: Twenty-two articles were included: 8 non-RCTs and 14 RCTs. No relevant travel fatigue papers were found. For jet lag, only 12 athlete-specific studies were available (six non-RCTs, six RCTs). In total (athletes and healthy populations), 11 non-pharmacological studies (participants 600; intervention group 290; four non-RCTs, seven RCTs) and 11 pharmacological studies (participants 1202; intervention group 870; four non-RCTs, seven RCTs) were included. For non-pharmacological interventions, seven studies across interventions related to actual travel and four to simulated travel. For pharmacological interventions, eight studies were based on actual travel and three on simulated travel. CONCLUSIONS: We found no literature pertaining to the management of travel fatigue. Evidence for the successful management of jet lag in athletes was of low quality. More field-based studies specifically on athlete populations are required with a multifaceted approach, better design and implementation to draw valid conclusions. PROSPERO registration number The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42019126852).


Assuntos
Síndrome do Jet Lag/terapia , Esportes , Benzodiazepinas/uso terapêutico , Ritmo Circadiano , Terapia por Exercício , Glucocorticoides/uso terapêutico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Hipnóticos e Sedativos/uso terapêutico , Síndrome do Jet Lag/tratamento farmacológico , Síndrome do Jet Lag/fisiopatologia , Luz , Refeições , Melatonina/análogos & derivados , Melatonina/uso terapêutico , Sono , Promotores da Vigília/uso terapêutico
12.
Ann Pharmacother ; 54(10): 1016-1020, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32270686

RESUMO

OBJECTIVE: The purpose of this article is to review the available clinical trial data that led to the Food and Drug Administration (FDA) approval of solriamfetol as well as its role in clinical practice. DATA SOURCES: A MEDLINE/PubMed search was conducted (January 2000 to February 2020) using the keyword solriamfetol to discover appropriate clinical trials. STUDY SELECTION AND DATA EXTRACTION: Articles were included that were published in the English language and related to the FDA approval of solriamfetol or provided novel information regarding this drug entity. DATA SYNTHESIS: The findings of the review show that solriamfetol may be a safe and effective option for the treatment of excessive sleepiness (ES) related to narcolepsy and obstructive sleep apnea (OSA). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Solriamfetol is distinguished from other stimulants in that it has lower binding affinity to dopamine and norepinephrine transporters and does not have the monoamine-releasing effects of amphetamines at usual therapeutic doses. Because of solriamfetol's unique mechanism of action, there may be a reduction in abuse potential compared with the other currently FDA-approved options. CONCLUSIONS: In clinical trials, solriamfetol has shown dose-dependent improvement in wakefulness over placebo and adds another option for clinicians when treating ES in narcolepsy and OSA.


Assuntos
Carbamatos/uso terapêutico , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Narcolepsia/complicações , Fenilalanina/análogos & derivados , Apneia Obstrutiva do Sono/complicações , Promotores da Vigília/uso terapêutico , Carbamatos/administração & dosagem , Carbamatos/farmacocinética , Ensaios Clínicos como Assunto , Distúrbios do Sono por Sonolência Excessiva/etiologia , Humanos , Narcolepsia/tratamento farmacológico , Fenilalanina/administração & dosagem , Fenilalanina/farmacocinética , Fenilalanina/uso terapêutico , Apneia Obstrutiva do Sono/tratamento farmacológico , Sonolência , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Promotores da Vigília/administração & dosagem , Promotores da Vigília/farmacocinética
13.
Chest ; 158(2): 776-786, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32147246

RESUMO

OSA is a highly prevalent sleep disorder, and subjective excessive daytime sleepiness (EDS) is the cardinal symptom for which many individuals seek medical advice. Positive airway pressure (PAP) devices, first-line treatment for OSA, eliminates EDS in most patients. However, a subset of patients suffers from persistent EDS despite adherence to therapy. Multiple conditions, some reversible, could account for the residual sleepiness and need to be explored, requiring detailed history, review of PAP data from the smart card, and sometimes additional testing. When all known causes of EDS are excluded, in adequately treated subjects, the purported mechanisms could relate to long-term exposure to the OSA-related sleep fragmentation, sleep deprivation, and hypoxic injury to the arousal system, shifts in melatonin secretion, or altered microbiome. Independent of the mechanism, in well-treated OSA, pharmacological therapy with approved drugs can be considered. Modafinil is commonly prescribed to combat residual EDS, but more recently two drugs, solriamfetol, a dual dopamine-norepinephrine reuptake inhibitor, and pitolisant, a histamine H3 receptor inverse agonist, were approved for EDS. Solriamfetol has undergone randomized controlled trials for treatment of EDS associated with both OSA and narcolepsy, exhibiting robust efficacy. Solriamfetol is renally excreted, with no known drug interactions. Pitolisant, which is nonscheduled, has undergone multiple RCTs in narcolepsy, showing improvement in subjective and objective EDS and one OSA trial showing improvement in subjective EDS.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Distúrbios do Sono por Sonolência Excessiva/etiologia , Apneia Obstrutiva do Sono/complicações , Promotores da Vigília/uso terapêutico , Carbamatos , Humanos , Modafinila , Fenilalanina/análogos & derivados , Piperidinas
14.
Drug Chem Toxicol ; 43(4): 373-377, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30293447

RESUMO

The demands imposed by today's world require a fast and efficient society, then, significant section of the population looks for support from psychotropic medicine. Modafinil is a psychostimulant that promotes wakefulness, it being recommended for treatment of narcolepsy, obstructive sleep apnea, and shift-work sleep disorder, besides being a cognitive function potentiator. However, chemical components of drugs can alter genetic material. Thus, the present study evaluated the cytotoxic and clastogenic/mutagenic potential of 0.25, 0.50, and 0.75 mg of Modafinil/mL of corn oil/100g body weight in acute treatments and subacute treatments, 15 days, to Rattus norvegicus, treated via gavage in a single daily dose. The drug was not cytotoxic at any of the evaluated doses in either of the treatments. However, the medicine showed clastogenic/mutagenic activity in the acute treatment group at the standard dose and at double dose. Data from the present study indicates that there should be greater caution as to the use of this psychostimulant by human beings.


Assuntos
Modafinila/toxicidade , Mutagênese , Mutagênicos/toxicidade , Promotores da Vigília/toxicidade , Animais , Aberrações Cromossômicas/induzido quimicamente , Masculino , Índice Mitótico , Ratos , Ratos Wistar
15.
Pain ; 161(2): 288-299, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31651580

RESUMO

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Because sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining, and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin- and parvalbumin-positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naive mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.


Assuntos
Córtex Cerebral/fisiopatologia , Ritmo Delta/fisiologia , Hiperalgesia/fisiopatologia , Neuralgia/fisiopatologia , Limiar da Dor/fisiologia , Sono/fisiologia , Inibidores da Captação Adrenérgica/farmacologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Antagonistas Colinérgicos/farmacologia , Sincronização Cortical/efeitos dos fármacos , Sincronização Cortical/fisiologia , Ritmo Delta/efeitos dos fármacos , Eletroencefalografia , Eletromiografia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/metabolismo , Hiperalgesia/metabolismo , Camundongos , Modafinila/farmacologia , Neuralgia/metabolismo , Limiar da Dor/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reserpina/farmacologia , Nervo Isquiático/cirurgia , Escopolamina/farmacologia , Sono/efeitos dos fármacos , Privação do Sono/induzido quimicamente , Privação do Sono/fisiopatologia , Promotores da Vigília/farmacologia
16.
Med Hypotheses ; 134: 109434, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634772

RESUMO

Dexamethasone has been observed to cause night-time wakefulness without accompanying fatigue. It is proposed here that the drug interrupts a sleep signal, and that although sleep has an ultimate ecological function, this signal is a proximate mechanism but not an ultimate physiological necessity, such that sleep is not a necessity.


Assuntos
Modelos Neurológicos , Sono/fisiologia , Adaptação Fisiológica , Citocinas/fisiologia , Dexametasona/farmacologia , Fadiga/tratamento farmacológico , Fadiga/fisiopatologia , Humanos , Sono/efeitos dos fármacos , Privação do Sono/fisiopatologia , Vigília/fisiologia , Promotores da Vigília/farmacologia , Promotores da Vigília/uso terapêutico , Ácido gama-Aminobutírico/fisiologia
17.
Intern Med ; 59(4): 577-579, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31611526

RESUMO

A 67-year-old woman with neuromyelitis optica spectrum disorder (NMOSD) developed severe somnolence. Ten days after admission, fluid-attenuated inversion-recovery magnetic resonance imaging (MRI) revealed hyperintense areas around the bilateral hypothalamus, which were not present on MRI at admission. The orexin level, which is decreased in idiopathic narcolepsy, was slightly decreased in her cerebrospinal fluid. Immunosuppressive treatment and methylphenidate markedly improved her somnolence. This case shows that NMOSD in the acute phase can cause somnolence in a patient without apparent lesions in the hypothalamus.


Assuntos
Metilfenidato/uso terapêutico , Modafinila/uso terapêutico , Narcolepsia/tratamento farmacológico , Narcolepsia/etiologia , Neuromielite Óptica/complicações , Neuromielite Óptica/fisiopatologia , Subtálamo/anormalidades , Idoso , Estimulantes do Sistema Nervoso Central/uso terapêutico , Feminino , Humanos , Japão , Imageamento por Ressonância Magnética/métodos , Narcolepsia/fisiopatologia , Sonolência , Subtálamo/diagnóstico por imagem , Subtálamo/fisiopatologia , Resultado do Tratamento , Promotores da Vigília/uso terapêutico
18.
Brain Res Bull ; 155: 166-173, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31838151

RESUMO

Cannabidiolic acid methyl ester (HU-580) is a more stable compound than cannabidiolic acid (CBDA) which has been shown to be effective in reducing nausea, anxiety, depression behaviors in animal models. Here we extend the investigation of this compound to determine its effect on the sleep-wake cycle in male Wistar rats. HU-580 dose-dependently (0.1, 1.0 or 100 µg/Kg, i.p.) prolonged wakefulness (W) and decreased slow wave sleep (SWS) duration whereas rapid eye movement sleep (REMS) showed no statistical change. In addition, the brain microdialysis probes either placed at nucleus accumbens (NAc) or into the basal forebrain in freely moving animals were used to evaluate the effects of HU-580 treatment on neurotransmitters related to the sleep-wake cycle modulation. HU-580 enhanced extracellular levels of dopamine, serotonin collected from NAc while adenosine and acetylcholine were increased in basal forebrain. In summary, HU-580 seems to possess wake-promoting pharmacological properties and enhances the levels of wake-related neurochemicals. This is the first report of effects of HU-580 on sleep modulation expanding the very limited existent data on the neurobiological effects of HU-580 on rats.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Canabinoides/administração & dosagem , Sono/efeitos dos fármacos , Promotores da Vigília/administração & dosagem , Acetilcolina/metabolismo , Adenosina/metabolismo , Animais , Monoaminas Biogênicas/metabolismo , Masculino , Microdiálise , Ratos Wistar , Vigília/efeitos dos fármacos
19.
Biol Aujourdhui ; 213(3-4): 87-108, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31829930

RESUMO

Narcolepsy-cataplexy was first described in the late 19th century in Germany and France. Prevalence was established to be 0.05 % and a canine model was discovered in the 1970s. In 1983, a Japanese study found that all patients carried HLA-DR2, suggesting autoimmunity as the cause of the disease. Studies in the canine model established that dopaminergic stimulation underlies anti-narcoleptic action of psychostimulants, while antidepressants were found to suppress cataplexy through adrenergic reuptake inhibition. No HLA association was found in canines. A linkage study initiated in 1988 revealed in hypocretin (orexin) receptor two mutations as the cause of canine narcolepsy in 1999. In 1992, studies on African Americans showed that DQ0602 was a better marker than DR2 across all ethnic groups. In 2000, hypocretin-1/orexin A levels were measured in the cerebrospinal fluid (CSF) and found to be undetectable in most patients, establishing hypocretin deficiency as the cause of narcolepsy. Decreased CSF hypocretin-1 was then found to be secondary to the loss of the 70,000 neurons producing hypocretin in the hypothalamus, suggesting immune destruction of these cells as the cause of the disease. Additional genetic studies, notably genome wide associations (GWAS), found multiple genetic predisposing factors for narcolepsy. These were almost all involved in other autoimmune diseases, although a strong and unique association with T cell receptor (TCR) alpha and beta loci were observed. Nonetheless, all attempts to demonstrate presence of autoantibodies against hypocretin cells in narcolepsy failed, and the presumed autoimmune cause remained unproven. In 2009, association with strep throat infections were found, and narcolepsy onsets were found to occur more frequently in spring and summer, suggesting upper away infections as triggers. Following reports that narcolepsy cases were triggered by vaccinations and infections against influenza A 2009 pH1N1, a new pandemic strain that erupted in 2009, molecular mimicry with influenza A virus was suggested in 2010. This hypothesis was later confirmed by peptide screening showing higher activity of CD4+ T cell reactivity to a specific post-translationally amidated segment of hypocretin (HCRT-NH2) and cross-reactivity of specific TCRs with a pH1N1-specific segment of hemagglutinin that shares homology with HCRT-NH2. Strikingly, the most frequent TCR recognizing these antigens was found to carry sequences containing TRAJ24 or TRVB4-2, segments modulated by narcolepsy-associated genetic polymorphisms. Cross-reactive CD4+ T cells with these cross-reactive TCRs likely subsequently recruit CD8+ T cells that are then involved in hypocretin cell destruction. Additional flu mimics are also likely to be discovered since narcolepsy existed prior to 2009. The work that has been conducted over the years on narcolepsy offers a unique perspective on the conduct of research on the etiopathogeny of a specific disease.


Assuntos
Epitopos/química , Mimetismo Molecular , Narcolepsia , Orthomyxoviridae/imunologia , Linfócitos T/imunologia , Promotores da Vigília/isolamento & purificação , Animais , Autoimunidade/imunologia , Pesquisa Biomédica/história , Cães , Epitopos/imunologia , História do Século XX , História do Século XXI , Humanos , Influenza Humana/imunologia , Narcolepsia/etiologia , Narcolepsia/história , Narcolepsia/imunologia , Neurologia/história , Neuropeptídeos/isolamento & purificação , Vigília/fisiologia
20.
Work ; 64(4): 843-852, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815724

RESUMO

BACKGROUND: Employment rates for people with HIV/AIDS are low, compared to the general population. One widespread barrier is fatigue, accompanied by daytime sleepiness and a lack of stamina. Previous pharmacological studies have demonstrated improvement of fatigue-related symptoms without affecting work-related goal attainmentOBJECTIVE:In this pilot study, we sought to determine whether a pharmacologic-behavioral two-phase combined approach could facilitate returning to work. METHODS: HIV+ participants with fatigue were treated with armodafinil. If energy improved, 8 sessions of biweekly manualized Behavioral Activation (BA) counseling were added to medication maintenance. Outcome was assessed on a 3-point scale along with clinician and self-ratings. RESULTS: Of the 46 participants enrolled in BA, 15 (33%) did not complete all 8 sessions: 6 got jobs so they no longer needed counseling; 4 did not like BA, and 5 dropped out for reasons such as moving away or substance use relapse. Of the 46, 29 (63%) attained their vocational goal and showed significant changes on self-report scales. CONCLUSIONS: Our integrated treatment including armodafinil plus BA counseling significantly increased the success of achieving work-related goals. The two-phase medication plus counseling program was well-tolerated by participants and the manualized BA counseling was readily applied by counselors without advanced mental health training, making the method potentially feasible in community settings.


Assuntos
Terapia Comportamental , Fadiga/tratamento farmacológico , Infecções por HIV/complicações , Retorno ao Trabalho , Adulto , Aconselhamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modafinila/administração & dosagem , Modafinila/uso terapêutico , Projetos Piloto , Promotores da Vigília/administração & dosagem , Promotores da Vigília/uso terapêutico
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