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Pesquisa : D27.505.519.625.663 [Categoria DeCS]
Referências encontradas : 205 [refinar]
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[PMID]:27771284
[Au] Autor:Moorman DE; James MH; Kilroy EA; Aston-Jones G
[Ad] Endereço:Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Psychological and Brain Sciences & Neuroscience and Behavior Graduate Program, University of Massachusetts Amherst, Amherst, MA 01003, USA. Electronic address: moorman@cns.umass.edu.
[Ti] Título:Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats.
[So] Source:Brain Res;1654(Pt A):34-42, 2017 Jan 01.
[Is] ISSN:1872-6240
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low-alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self-administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the OX1R may be an important target for treating alcohol abuse.
[Mh] Termos MeSH primário: Consumo de Bebidas Alcoólicas/tratamento farmacológico
Benzoxazóis/farmacologia
Depressores do Sistema Nervoso Central/administração & dosagem
Comportamento de Procura de Droga/efeitos dos fármacos
Etanol/administração & dosagem
Antagonistas dos Receptores de Orexina/farmacologia
Ureia/análogos & derivados
[Mh] Termos MeSH secundário: Consumo de Bebidas Alcoólicas/metabolismo
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico
Transtornos Relacionados ao Uso de Álcool/metabolismo
Animais
Animais não Endogâmicos
Condicionamento Operante/efeitos dos fármacos
Condicionamento Operante/fisiologia
Sinais (Psicologia)
Modelos Animais de Doenças
Comportamento de Procura de Droga/fisiologia
Masculino
Motivação/efeitos dos fármacos
Motivação/fisiologia
Receptores de Orexina/metabolismo
Ratos Sprague-Dawley
Autoadministração
Ureia/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea); 0 (Benzoxazoles); 0 (Central Nervous System Depressants); 0 (Hcrtr1 protein, rat); 0 (Orexin Receptor Antagonists); 0 (Orexin Receptors); 3K9958V90M (Ethanol); 8W8T17847W (Urea)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:180101
[Lr] Data última revisão:
180101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161025
[St] Status:MEDLINE


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[PMID]:28910447
[Au] Autor:Qiao SN; Zhou W; Liu LL; Zhang DQ; Zhong YM
[Ad] Endereço:Institutes of Brain Science, Fudan University, Shanghai, China.
[Ti] Título:Orexin-A Suppresses Signal Transmission to Dopaminergic Amacrine Cells From Outer and Inner Retinal Photoreceptors.
[So] Source:Invest Ophthalmol Vis Sci;58(11):4712-4721, 2017 Sep 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: The neuropeptides orexin-A and orexin-B are widely expressed in the vertebrate retina; however, their role in visual function is unclear. This study investigates whether and how orexins modulate signal transmission to dopaminergic amacrine cells (DACs) from both outer retinal photoreceptors (rods and cones) and inner retinal photoreceptors (melanopsin-expressing intrinsically photosensitive retinal ganglion cells [ipRGCs]). Methods: A whole-cell voltage-clamp technique was used to record light-induced responses from genetically labeled DACs in flat-mount mouse retinas. Rod and cone signaling to DACs was confirmed pharmacologically (in wild-type retinas), whereas retrograde melanopsin signaling to DACs was isolated either pharmacologically (in wild-type retinas) or by genetic deletion of rod and cone function (in transgenic mice). Results: Orexin-A attenuated rod/cone-mediated light responses in the majority of DACs and inhibited all DACs that exhibited melanopsin-based light responses, suggesting that exogenous orexin suppresses signal transmission from rods, cones, and ipRGCs to DACs. In addition, orexin receptor 1 antagonist SB334867 and orexin receptor 2 antagonist TCS OX229 enhanced melanopsin-based DAC responses, indicating that endogenous orexins inhibit signal transmission from ipRGCs to DACs. We further found that orexin-A inhibits melanopsin-based DAC responses via orexin receptors on DACs, whereas orexin-A may modulate signal transmission from rods and cones to DACs through activation of orexin receptors on DACs and their upstream neurons. Conclusions: Our results suggest that orexins could influence visual function via the dopaminergic system in the mammalian retina.
[Mh] Termos MeSH primário: Células Amácrinas/metabolismo
Dopamina/metabolismo
Orexinas/farmacologia
Células Fotorreceptoras de Vertebrados/metabolismo
Células Ganglionares da Retina/metabolismo
Opsinas de Bastonetes/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Benzoxazóis/farmacologia
Feminino
Isoquinolinas/farmacologia
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Antagonistas dos Receptores de Orexina/farmacologia
Técnicas de Patch-Clamp
Piridinas/farmacologia
Ureia/análogos & derivados
Ureia/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea); 0 (1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone); 0 (Benzoxazoles); 0 (Isoquinolines); 0 (Orexin Receptor Antagonists); 0 (Orexins); 0 (Pyridines); 0 (Rod Opsins); 0 (melanopsin); 8W8T17847W (Urea); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170915
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-21835


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[PMID]:28739044
[Au] Autor:Yamamoto N; Ohrui S; Okada T; Yata M; Saitoh T; Kutsumura N; Nagumo Y; Irukayama-Tomobe Y; Ogawa Y; Ishikawa Y; Watanabe Y; Hayakawa D; Gouda H; Yanagisawa M; Nagase H
[Ad] Endereço:International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
[Ti] Título:Essential structure of orexin 1 receptor antagonist YNT-707, Part I: Role of the 4,5-epoxy ring for binding with orexin 1 receptor.
[So] Source:Bioorg Med Chem Lett;27(17):4176-4179, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The essential structure of the orexin 1 receptor (OX R) antagonist YNT-707 (2) was clarified, particularly the roles to OX R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6ß-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring. Finally, we proposed the difference in the active conformation between OX R and κ opioid receptor (KOR), especially in the orientation of the 6-amide group which is expected to be a useful guide for medicinal chemists to design OX R ligands.
[Mh] Termos MeSH primário: Compostos de Epóxi/farmacologia
Morfinanos/farmacologia
Antagonistas dos Receptores de Orexina/farmacologia
Receptores de Orexina/metabolismo
Sulfonamidas/farmacologia
[Mh] Termos MeSH secundário: Sítios de Ligação/efeitos dos fármacos
Relação Dose-Resposta a Droga
Compostos de Epóxi/química
Seres Humanos
Estrutura Molecular
Morfinanos/síntese química
Morfinanos/química
Antagonistas dos Receptores de Orexina/síntese química
Antagonistas dos Receptores de Orexina/química
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Epoxy Compounds); 0 (Morphinans); 0 (Orexin Receptor Antagonists); 0 (Orexin Receptors); 0 (Sulfonamides); 0 (YNT-707)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE


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[PMID]:28663311
[Au] Autor:Treiber A; de Kanter R; Roch C; Gatfield J; Boss C; von Raumer M; Schindelholz B; Muehlan C; van Gerven J; Jenck F
[Ad] Endereço:Departments of Preclinical Drug Metabolism and Pharmacokinetics (A.T., R.d.K.), Preclinical Pharmacology (C.R., F.J.), Biology (J.G.), Chemistry (C.B.), Clinical Pharmacology (C.M.), and Preclinical Development (M.v.R., B.S.), Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland; Center for Human Dru
[Ti] Título:The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468.
[So] Source:J Pharmacol Exp Ther;362(3):489-503, 2017 Sep.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX and OX ) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.
[Mh] Termos MeSH primário: Encéfalo/efeitos dos fármacos
Encéfalo/fisiologia
Descoberta de Drogas/métodos
Antagonistas dos Receptores de Orexina/farmacocinética
[Mh] Termos MeSH secundário: Animais
Células CHO
Cricetinae
Cricetulus
Cães
Relação Dose-Resposta a Droga
Método Duplo-Cego
Seres Humanos
Masculino
Ratos
Ratos Wistar
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Orexin Receptor Antagonists)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.241596


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[PMID]:28631980
[Au] Autor:Boss C; Roch C
[Ad] Endereço:a Drug Discovery and Preclinical Research , Actelion Pharmaceuticals Ltd , Allschwil , Switzerland.
[Ti] Título:Orexin research: patent news from 2016.
[So] Source:Expert Opin Ther Pat;27(10):1123-1133, 2017 Oct.
[Is] ISSN:1744-7674
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The orexin system consists of two G-protein-coupled receptors, orexin 1 and orexin 2 and two endogenous ligands, orexin A and orexin B . It is evolutionarily highly conserved. It is involved in the promotion of wakefulness as well as in anxiety and addictive disorders. In addition, its activation via the Ox1 receptor triggers apoptosis in several cancer cell lines. Dual orexin receptor antagonists are successfully used to treat primary insomnia. The major open questions are now related to the clinical validation of Ox1 selective antagonists. A strong rationale exists for orexin agonism in the treatment of narcolepsy with cataplexy. Areas covered: The patent applications from Thomson Reuters Integrity Database added in 2016 are summarized and discussed together with the most important findings published in the scientific literature. Expert opinion: The large number of patents shows the continuing interest in the orexin receptors as targets. The structural scope covered is narrow. Questions about novelty and inventiveness are evident. The additional information published on X-ray structures on both orexin receptors opens new ways of optimizing antagonists. It might also influence the efforts in the identification of orexin receptor agonists. Being potential treatments for narcolepsy with cataplexy.
[Mh] Termos MeSH primário: Desenho de Drogas
Receptores de Orexina/efeitos dos fármacos
Orexinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Ligantes
Antagonistas dos Receptores de Orexina/farmacologia
Receptores de Orexina/metabolismo
Patentes como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Ligands); 0 (Orexin Receptor Antagonists); 0 (Orexin Receptors); 0 (Orexins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1080/13543776.2017.1344221


  6 / 205 MEDLINE  
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[PMID]:28559480
[Au] Autor:Beuckmann CT; Suzuki M; Ueno T; Nagaoka K; Arai T; Higashiyama H
[Ad] Endereço:Neurology Business Group, Discovery (C.T.B.), Drug Metabolism and Pharmacokinetics (T.U.), hhc Data Creation Center (K.N.), and Medicine Development Center (T.A.), Eisai Co., Ltd., Tsukuba, Ibaraki, Japan; and Global Regulatory Affairs (M.S.), Neurology Business Group (H.H.), Japan and Asia Clinical
[Ti] Título:In Vitro and In Silico Characterization of Lemborexant (E2006), a Novel Dual Orexin Receptor Antagonist.
[So] Source:J Pharmacol Exp Ther;362(2):287-295, 2017 Aug.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Orexin (hypocretin) neuropeptides have, among others, been implicated in arousal/sleep control, and antagonizing the orexin signaling pathway has been previously demonstrated to promote sleep in animals and humans. This mechanism opens up a new therapeutic approach to curb excessive wakefulness in insomnia disorder rather than to promote sleep-related signaling. Here we describe the preclinical pharmacological in vitro and in silico characterization of lemborexant ((1 ,2 )-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)- -(5-fluoropyridin-2-yl)cyclopropanecarboxamide)), a dual orexin receptor antagonist (DORA), as a novel experimental therapeutic agent for the symptomatic treatment of insomnia disorder and compare its properties to two other DORAs, almorexant and suvorexant. Lemborexant binds to both orexin receptors and functionally inhibits them in a competitive manner with low nanomolar potency, without any species difference apparent among human, rat, and mouse receptors. Binding and dissociation kinetics on both orexin receptors are rapid. Lemborexant is selective for both orexin receptors over 88 other receptors, transporters, and ion channels of important physiologic function. In silico modeling of lemborexant into the orexin receptors showed that it assumes the same type of conformation within the receptor-binding pocket as suvorexant, the -stacked horseshoe-like conformation.
[Mh] Termos MeSH primário: Antagonistas dos Receptores de Orexina/metabolismo
Receptores de Orexina/metabolismo
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Células CHO
Simulação por Computador
Cricetinae
Cricetulus
Células HEK293
Seres Humanos
Camundongos
Antagonistas dos Receptores de Orexina/química
Receptores de Orexina/química
Estrutura Secundária de Proteína
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HCRTR1 protein, human); 0 (HCRTR2 protein, human); 0 (Orexin Receptor Antagonists); 0 (Orexin Receptors)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.117.241422


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[PMID]:28444767
[Au] Autor:Yao L; Ramirez AD; Roecker AJ; Fox SV; Uslaner JM; Smith SM; Hodgson R; Coleman PJ; Renger JJ; Winrow CJ; Gotter AL
[Ad] Endereço:Department of Neuroscience, Merck Research Laboratories, West Point, Pennsylvania, USA.
[Ti] Título:The dual orexin receptor antagonist, DORA-22, lowers histamine levels in the lateral hypothalamus and prefrontal cortex without lowering hippocampal acetylcholine.
[So] Source:J Neurochem;142(2):204-214, 2017 Jul.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA) receptor modulators, which promote sleep but are associated with a panoply of side effects, including cognitive and memory impairment. Dual orexin receptor antagonists (DORAs) have recently emerged as an alternative therapeutic approach that acts via a distinct and more selective wake-attenuating mechanism with the potential to be associated with milder side effects. Given their distinct mechanism of action, the current work tested the hypothesis that DORAs and GABA receptor modulators differentially regulate neurochemical pathways associated with differences in sleep architecture and cognitive performance induced by these pharmacological mechanisms. Our findings showed that DORA-22 suppresses the release of the wake neurotransmitter histamine in the lateral hypothalamus, prefrontal cortex, and hippocampus with no significant alterations in acetylcholine levels. In contrast, eszopiclone, commonly used as a GABA modulator, inhibited acetylcholine secretion across brain regions with variable effects on histamine release depending on the extent of wakefulness induction. In normal waking rats, eszopiclone only transiently suppressed histamine secretion, whereas this suppression was more obvious under caffeine-induced wakefulness. Compared with the GABA modulator eszopiclone, DORA-22 elicits a neurotransmitter profile consistent with wake reduction that does not impinge on neurotransmitter levels associated with cognition and rapid eye movement sleep.
[Mh] Termos MeSH primário: Acetilcolina/metabolismo
Hipocampo/efeitos dos fármacos
Histamina/metabolismo
Região Hipotalâmica Lateral/efeitos dos fármacos
Antagonistas dos Receptores de Orexina/farmacologia
Piperidinas/farmacologia
Córtex Pré-Frontal/efeitos dos fármacos
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Hipocampo/metabolismo
Masculino
Córtex Pré-Frontal/metabolismo
Ratos
Sono/efeitos dos fármacos
Sono/fisiologia
Distúrbios do Início e da Manutenção do Sono/fisiopatologia
Vigília/efeitos dos fármacos
Ácido gama-Aminobutírico/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DORA-22); 0 (Orexin Receptor Antagonists); 0 (Piperidines); 0 (Triazoles); 56-12-2 (gamma-Aminobutyric Acid); 820484N8I3 (Histamine); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170810
[Lr] Data última revisão:
170810
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.14055


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[PMID]:28364509
[Au] Autor:Roth T; Black J; Cluydts R; Charef P; Cavallaro M; Kramer F; Zammit G; Walsh J
[Ad] Endereço:Thomas Roth Sleep Disorders and Research Center, Detroit, MI.
[Ti] Título:Dual Orexin Receptor Antagonist, Almorexant, in Elderly Patients With Primary Insomnia: A Randomized, Controlled Study.
[So] Source:Sleep;40(2), 2017 Feb 01.
[Is] ISSN:1550-9109
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Objective: Sleep laboratory study to determine the dose-related efficacy and safety of almorexant in elderly patients with primary chronic insomnia. Methods: Patients aged ≥65 years with primary insomnia were enrolled into a prospective, randomized, double-blind, placebo-controlled, multicenter dose-finding study with a five-period, five-way Latin square cross-over design. Patients were randomized to one of 10 unique sequences of two-night treatment with oral almorexant 25, 50, 100, or 200 mg capsules, or matching placebo. The primary efficacy endpoint was polysomnography (PSG)-determined mean wake time after sleep onset (WASO). Secondary and exploratory efficacy endpoints were also assessed. Results: 112 patients were randomized (mean [SD] age 72.1 [5.0] years; 69.9% female). Significant, dose-related improvements (reductions) in mean WASO were observed with almorexant. Least-squares mean (95% CI) treatment effects in the almorexant 200, 100, 50, and 25 mg dose groups versus placebo were -46.5 minutes (-53.0, -39.9; p < .0001), -31.4 minutes (-38.0, -24.9; p < .0001), -19.2 minutes (-25.7, -12.6; p < .0001), and -10.4 minutes (-17.0, -3.9; p = .0018), respectively. Mean total sleep time was significantly increased with each almorexant dose (mean increases versus placebo ranged 55.1-14.3 minutes; p < .0001 for each dose). Latency to persistent sleep was statistically significantly reduced only with almorexant 200 mg versus placebo (mean [95% CI] treatment effect -10.2 minutes, [-15.4, -5.0]; p = .0001). No unexpected safety concerns were identified. Adverse events were similar between all almorexant dose groups and placebo. Conclusions: Two-night oral administration of almorexant was effective and well tolerated in treating primary insomnia in elderly patients.
[Mh] Termos MeSH primário: Acetamidas/uso terapêutico
Isoquinolinas/uso terapêutico
Antagonistas dos Receptores de Orexina/uso terapêutico
Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Doença Crônica
Estudos Cross-Over
Relação Dose-Resposta a Droga
Método Duplo-Cego
Esquema de Medicação
Feminino
Seguimentos
Seres Humanos
Masculino
Polissonografia
Estudos Prospectivos
Distúrbios do Início e da Manutenção do Sono/diagnóstico
Fatores de Tempo
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Acetamides); 0 (Isoquinolines); 0 (Orexin Receptor Antagonists); 9KCW39P2EI (almorexant)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170402
[St] Status:MEDLINE
[do] DOI:10.1093/sleep/zsw034


  9 / 205 MEDLINE  
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[PMID]:28364414
[Au] Autor:Ng MC
[Ad] Endereço:Section of Neurology, Department of Internal Medicine, Health Sciences Centre, University of Manitoba, Winnipeg, MB, Canada.
[Ti] Título:Orexin and Epilepsy: Potential Role of REM Sleep.
[So] Source:Sleep;40(3), 2017 Mar 01.
[Is] ISSN:1550-9109
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Interest in orexin receptor antagonism as a novel mechanism of action against seizures and epilepsy has increased in recent years. Loss of orexinergic activity is associated with rapid eye movement (REM) sleep onset, and REM sleep is generally protective against seizures. This paper discusses the dynamic modulation of seizure threshold by orexin through a postulated "orexi-cortical" axis in which the specific type of orexinergic activity exquisitely regulates sleep-wake states to modify ascending subcortical influences on cortical synchronization with profound subsequent consequences on seizure threshold. This paper also explores the current state of research into experimental orexinergic modulation of seizure threshold and suggests possible future research directions to fully understand the promise and peril of orexinergic manipulation in seizures and epilepsy.
[Mh] Termos MeSH primário: Epilepsia/fisiopatologia
Orexinas/fisiologia
Sono REM/fisiologia
[Mh] Termos MeSH secundário: Animais
Epilepsia/tratamento farmacológico
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/farmacologia
Peptídeos e Proteínas de Sinalização Intracelular/fisiologia
Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico
Neuropeptídeos/farmacologia
Neuropeptídeos/fisiologia
Neuropeptídeos/uso terapêutico
Antagonistas dos Receptores de Orexina/farmacologia
Antagonistas dos Receptores de Orexina/uso terapêutico
Orexinas/farmacologia
Orexinas/uso terapêutico
Sono/fisiologia
Sono REM/efeitos dos fármacos
Vigília/efeitos dos fármacos
Vigília/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Intracellular Signaling Peptides and Proteins); 0 (Neuropeptides); 0 (Orexin Receptor Antagonists); 0 (Orexins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170402
[St] Status:MEDLINE
[do] DOI:10.1093/sleep/zsw061


  10 / 205 MEDLINE  
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[PMID]:28296947
[Au] Autor:Khoo SY; McNally GP; Clemens KJ
[Ad] Endereço:School of Psychology, University of New South Wales, Sydney, Australia.
[Ti] Título:The dual orexin receptor antagonist TCS1102 does not affect reinstatement of nicotine-seeking.
[So] Source:PLoS One;12(3):e0173967, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The orexin/hypocretin system is important for appetitive motivation towards multiple drugs of abuse, including nicotine. Both OX1 and OX2 receptors individually have been shown to influence nicotine self-administration and reinstatement. Due to the increasing clinical use of dual orexin receptor antagonists in the treatment of disorders such as insomnia, we examined whether a dual orexin receptor antagonist may also be effective in reducing nicotine seeking. We tested the effect of intracerebroventricular (i.c.v.) administration of the potent and selective dual orexin receptor antagonist TCS1102 on orexin-A-induced food self-administration, nicotine self-administration and reinstatement of nicotine-seeking in rats. Our results show that 30 µg of TCS1102 i.c.v. abolishes orexin-A-induced increases in food self-administration but does not reduce nicotine self-administration. Neither i.c.v. 10 µg nor 30 µg of TCS1102 reduced compound reinstatement after short-term (15 days) self-administration nicotine, but 30 µg transiently reduced cue/nicotine compound reinstatement after chronic self-administration (29 days). These results indicate that TCS1102 has no substantial effect on motivation for nicotine seeking following chronic self-administration and no effect after shorter periods of intake. Orexin receptor antagonists may therefore have little clinical utility against nicotine addiction.
[Mh] Termos MeSH primário: Benzimidazóis/farmacologia
Comportamento de Procura de Droga/efeitos dos fármacos
Nicotina/administração & dosagem
Antagonistas dos Receptores de Orexina/farmacologia
Pirrolidinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Benzimidazóis/administração & dosagem
Injeções Intraventriculares
Antagonistas dos Receptores de Orexina/administração & dosagem
Pirrolidinas/administração & dosagem
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzimidazoles); 0 (Orexin Receptor Antagonists); 0 (Pyrrolidines); 0 (TCS 1102); 6M3C89ZY6R (Nicotine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170316
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173967



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