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https://www.readbyqxmd.com/read/28631980/orexin-research-patent-news-from-2016
#1
Christoph Boss, Catherine Roch
The orexin (hypocretin) system consists of two G-protein-coupled receptors, orexin 1 (Ox1) and orexin 2 (Ox2) and two endogenous peptidic ligands, orexin A (OxA) and orexin B (OxB). It is evolutionarily highly conserved. In the brain, it is involved in the promotion of wakefulness under motivational circumstances 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 (DORAs) such as suvorexant are successfully used to treat primary insomnia...
June 20, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28630298/hypocretin-orexin-is-critical-in-sustaining-theta-gamma-rich-waking-behaviors-that-drive-sleep-need
#2
Anne Vassalli, Paul Franken
Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas Hcrt(ko/ko) mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG δ (1.0 to 4.0 Hz) power rebound like WT littermates, spontaneous waking fails to induce a δ power reflecting prior waking duration. This correlates with impaired θ (6...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28619187/safety-and-efficacy-of-long-term-use-of-sodium-oxybate-for-narcolepsy-with-cataplexy-in-routine-clinical-practice
#3
Panagis Drakatos, Dimosthenis Lykouras, Grainne D'Ancona, Sean Higgins, Nadia Gildeh, Raluca Macavei, Ivana Rosenzweig, Joerg Steier, Adrian J Williams, Rexford Muza, Brian D Kent, Guy Leschziner
BACKGROUND: Sodium oxybate is licensed in Europe for the treatment of narcolepsy with cataplexy in adults. The aim of this study was to assess the efficacy and safety of sodium oxybate in clinical practice in patients with narcolepsy and cataplexy refractory to other treatments. MATERIALS AND METHODS: This was a retrospective single centre study including patients with severe narcolepsy with cataplexy refractory to other treatments, who were initiated on sodium oxybate between 2009 and 2015...
July 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28619176/evaluation-of-the-effect-of-jzp-110-in-patients-with-narcolepsy-assessed-using-the-maintenance-of-wakefulness-test-censored-to-20-minutes
#4
Chad Ruoff, Richard K Bogan, Helen Emsellem, Neil Feldman, Alan Lankford, Gary Bream, Moise Khayrallah, Yuan Lu, Lawrence P Carter, Jed Black
OBJECTIVE: To evaluate the effects of JZP-110 on the Maintenance of Wakefulness Test (MWT) with data censored to include only the first 20 min of a 40-min MWT. METHODS: In a 4-week, placebo-controlled crossover design (Study 201; N = 33) and a 12-week parallel-group design (Study 202; N = 93), JZP-110 was evaluated in narcolepsy patients using changes from baseline in the 40-min MWT as the primary endpoint. Effect sizes based on the change from baseline in mean MWT sleep latency were calculated using 20-min censored MWT data and compared to 40-min MWT data...
July 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28619175/sodium-oxybate-treatment-in-narcolepsy-and-its-effect-on-muscle-tone
#5
Geert Mayer, Andrea Rodenbeck, Karl Kesper
AIMS: To estimate the effect of the compound sodium oxybate (SO) on chin muscle tone in sleep, a re-analysis of the results of the international multicenter study SXB-15 was performed, applying a validated semi-automatic analysis of muscle tone. This analysis distinguishes short (<0.5 s) and long (>0.5 s) muscle activity indices per hour (SMI, LMI) in 116 patients with narcolepsy-cataplexy. While stable stimulant medication was permitted, tricyclics and SSRIs were withdrawn. Polysomnographies were performed at baseline (V5), four weeks after titration of SO to 4...
July 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28601291/absence-of-autoreactive-cd4-t-cells-targeting-hla-dqa1-01-02-dqb1-06-02-restricted-hypocretin-orexin-epitopes-in-narcolepsy-type-1-when-detected-by-elispot
#6
Birgitte Rahbek Kornum, Kristoffer Sølvsten Burgdorf, Anja Holm, Henrik Ullum, Poul Jennum, Stine Knudsen
Narcolepsy type 1, a neurological sleep disorder strongly associated with Human Leukocyte Antigen (HLA-)DQB1*06:02, is caused by the loss of hypothalamic neurons producing the wake-promoting neuropeptide hypocretin (hcrt, also known as orexin). This loss is believed to be caused by an autoimmune reaction. To test whether hcrt itself could be a possible target in the autoimmune attack, CD4(+) T-cell reactivity towards six different 15-mer peptides from prepro-hypocretin with high predicted affinity to the DQA1*01:02/DQB1*06:02 MHC class II dimer was tested using EliSpot in a cohort of 22 narcolepsy patients with low CSF hcrt levels, and 23 DQB1*06:02 positive healthy controls...
August 15, 2017: Journal of Neuroimmunology
https://www.readbyqxmd.com/read/28572475/symptomatic-narcolepsy-in-sj%C3%A3-gren-syndrome
#7
Eun-Kee Bae, Dan A Oh, Byung-Nam Yoon
No abstract text is available yet for this article.
June 2017: Journal of Rheumatology
https://www.readbyqxmd.com/read/28568319/narcolepsy-with-cataplexy-and-pregnancy-a-case-control-study
#8
Elena Calvo-Ferrandiz, Rosa Peraita-Adrados
This was a retrospective case-control study in 25 patients with narcolepsy with cataplexy and 75 women in the control group. Patients completed the questionnaire by Maurovich-Horvat et al. (J. Sleep Res., 2013, 22: 496-512). We personally interviewed 25 patients with narcolepsy with cataplexy using the administered questionnaire regarding conception, pregnancy, delivery, perinatal and breastfeeding periods. Patients with narcolepsy with cataplexy reported 59 pregnancies versus 164 in the control group. In 16 cases (27...
June 1, 2017: Journal of Sleep Research
https://www.readbyqxmd.com/read/28561068/gamma-hydroxybutyrate-increases-resting-state-limbic-perfusion-and-body-and-emotion-awareness-in-humans
#9
Oliver G Bosch, Fabrizio Esposito, Michael M Havranek, Dario Dornbierer, Robin von Rotz, Philipp Staempfli, Boris B Quednow, Erich Seifritz
Gamma-hydroxybutyrate (GHB) is a GHB-/GABA-B receptor agonist inducing a broad spectrum of subjective effects including euphoria, disinhibition, and enhanced vitality. It is used as treatment for neuropsychiatric disorders including narcolepsy and alcohol withdrawal, but is also a drug of abuse. Non-medical users report enhancement of body and emotion awareness during intoxication. However, the neuronal underpinnings of such awareness alterations under GHB are unknown so far. The assessment of regional cerebral blood flow (rCBF) by pharmacological magnetic resonance imaging (phMRI) enables the elucidation of drug-induced functional brain alterations...
May 31, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28551715/direct-comparison-of-the-acute-subjective-emotional-autonomic-and-endocrine-effects-of-mdma-methylphenidate-and-modafinil-in-healthy-subjects
#10
Patrick C Dolder, Felix Müller, Yasmin Schmid, Stefan J Borgwardt, Matthias E Liechti
RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally and investigated as an adjunct to psychotherapy. Methylphenidate and modafinil are psychostimulants that are used to treat attention-deficit/hyperactivity disorder and narcolepsy, respectively, but they are also misused as cognitive enhancers. Little is known about differences in the acute effects of equally cardiostimulant doses of these stimulant-type substances compared directly within the same subjects. METHODS: We investigated the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg), and placebo in a double-blind, cross-over study in 24 healthy participants...
May 27, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28549585/cystamine-mediated-inhibition-of-protein-disulfide-isomerase-triggers-aggregation-of-misfolded-orexin-a-in-the-golgi-apparatus-and-prevents-extracellular-secretion-of-orexin-a
#11
Issei Fujita, Mizuki Nobunaga, Takahiro Seki, Yuki Kurauchi, Akinori Hisatsune, Hiroshi Katsuki
Orexins (orexin-A and orexin-B) are neuropeptides that are reduced in narcolepsy, a sleep disorder that is characterized by excessive daytime sleepiness, sudden sleep attacks and cataplexy. However, it remains unclear how orexins in the brain and orexin neurons are reduced in narcolepsy. Orexin-A has two closely located intramolecular disulfide bonds and is prone to misfolding due to the formation of incorrect disulfide bonds. Protein disulfide isomerase (PDI) possesses disulfide interchange activity. PDI can modify misfolded orexin-A to its native form by rearrangement of two disulfide bonds...
May 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28544614/proteomic-profiling-of-the-hypothalamus-in-two-mouse-models-of-narcolepsy
#12
Sausan Azzam, Daniela Schlatzer, David Nethery, Dania Saleh, Xiaolin Li, Afaf Akladious, Mark R Chance, Kingman P Strohl
Narcolepsy is a disabling neurological disorder of sleepiness linked to the loss of neurons producing orexin neuropeptides in the hypothalamus. Two well characterized phenotypic mouse models of narcolepsy, loss-of-function (orexin-knockout) and progressive loss of orexin (orexin/ataxin-3) exist. The open question is whether the proteomics signatures of the hypothalamus would be different between the two models. To address this gap, we utilized a label-free proteomics approach and conducted a hypothalamic proteome analysis by comparing each disease model to that of wild type...
May 22, 2017: Proteomics
https://www.readbyqxmd.com/read/28537447/hypocretin-measurement-shelf-age-of-radioimmunoassay-kit-but-not-freezer-time-influences-assay-variability
#13
Glenda Keating, Donald L Bliwise, Prabhjyot Saini, David B Rye, Lynn Marie Trotti
The hypothalamic peptide hypocretin 1 (orexin A) may be assayed in cerebrospinal fluid to diagnose narcolepsy type 1. This testing is not commercially available, and factors contributing to assay variability have not previously been comprehensively explored. In the present study, cerebrospinal fluid hypocretin concentrations were determined in duplicate in 155 patient samples, across a range of sleep disorders. Intra-assay variability of these measures was analyzed. Inter-assay correlation between samples tested at Emory and at Stanford was high (r = 0...
May 24, 2017: Scandinavian Journal of Clinical and Laboratory Investigation
https://www.readbyqxmd.com/read/28526554/the-roles-of-orexins-in-sleep-wake-regulation
#14
REVIEW
Michihiro Mieda
Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). A deficiency of orexin signaling results in the sleep disorder narcolepsy-cataplexy in humans, dogs, and rodents, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. Multiple approaches, including molecular genetic, electrophysiological, pharmacological, and neuroanatomical studies have suggested that orexins play critical roles in the maintenance of wakefulness by regulating the function of monoaminergic and cholinergic neurons that are implicated in the regulation of wakefulness...
May 16, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28526553/hypothalamic-regulation-of-the-sleep-wake-cycle
#15
REVIEW
Daisuke Ono, Akihiro Yamanaka
Sleep is one of the most important physiological functions in mammals. It is regulated by not only homeostatic regulation but also circadian clock. Several neuropeptide-producing neurons located in the hypothalamus are implicated in the regulation of sleep/wakefulness. Among them, orexin/hypocretin-producing neurons (orexin neurons) are a crucial component for maintenance of wakefulness, because lack of orexin function results in narcolepsy, which is a sleep disorder. Recent findings have identified substances that excite or inhibit neural activity of orexin neurons...
May 17, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28522102/retrospective-multicenter-matched-case-control-study-on-the-risk-factors-for-narcolepsy-with-special-focus-on-vaccinations-including-pandemic-influenza-vaccination-and-infections-in-germany
#16
Doris Oberle, Jutta Pavel, Geert Mayer, Peter Geisler, Brigitte Keller-Stanislawski
OBJECTIVE: Studies associate pandemic influenza vaccination with narcolepsy. In Germany, a retrospective, multicenter, matched case-control study was performed to identify risk factors for narcolepsy, particularly regarding vaccinations (seasonal and pandemic influenza vaccination) and infections (seasonal and pandemic influenza) and to quantify the detected risks. METHODS: Patients with excessive daytime sleepiness who had been referred to a sleep center between April 2009 and December 2012 for multiple sleep latency test (MSLT) were eligible...
June 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28522101/cardiovascular-fitness-in-narcolepsy-is-inversely-related-to-sleepiness-and-the-number-of-cataplexy-episodes
#17
Martin Matoulek, Vladimír Tuka, Magdalena Fialová, Soňa Nevšímalová, Karel Šonka
OBJECTIVE: Cardiopulmonary fitness depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy spent more time being sleepy or asleep than controls; thus we may speculate that they have a lower quantity and quality of physical activity. The aim of the present study was thus to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness. PATIENTS AND METHODS: The cross-sectional study included 32 patients with narcolepsy with cataplexy, 10 patients with narcolepsy without cataplexy, and 36 age- and gender-matched control subjects, in whom a symptom-limited exercise stress test with expired gas analysis was performed...
June 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28522097/sleep-spindle-density-in-narcolepsy
#18
Julie Anja Engelhard Christensen, Miki Nikolic, Mathias Hvidtfelt, Birgitte Rahbek Kornum, Poul Jennum
BACKGROUND: Patients with narcolepsy type 1 (NT1) show alterations in sleep stage transitions, rapid-eye-movement (REM) and non-REM sleep due to the loss of hypocretinergic signaling. However, the sleep microstructure has not yet been evaluated in these patients. We aimed to evaluate whether the sleep spindle (SS) density is altered in patients with NT1 compared to controls and patients with narcolepsy type 2 (NT2). METHODS: All-night polysomnographic recordings from 28 NT1 patients, 19 NT2 patients, 20 controls (C) with narcolepsy-like symptoms, but with normal cerebrospinal fluid hypocretin levels and multiple sleep latency tests, and 18 healthy controls (HC) were included...
June 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28522087/mazindol-a-risk-factor-for-pulmonary-arterial-hypertension
#19
Eric Konofal, Cherine Benzouid, Christophe Delclaux, Michel Lecendreux, Elizabeth Hussey
Mazindol is an imidazo-isoindole derivative, a tricyclic compound and a non-amphetamine central nervous system stimulant that blocks dopamine and norepinephrine reuptake. Mazindol was withdrawn from the US and European markets in 1999 for reasons unrelated to its efficacy or safety around a time when other anorexic drugs were found to be associated with the development of pulmonary arterial hypertension (PAH). Despite the use of mazindol for decades, reports of PAH due to mazindol intake have been extremely rare...
June 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28522076/sleep-wake-stability-in-narcolepsy-patients-with-normal-low-and-unmeasurable-hypocretin-levels
#20
Mathias Hvidtfelt Hansen, Birgitte Rahbek Kornum, Poul Jennum
OBJECTIVE: To compare diurnal and nocturnal electrophysiological data from narcolepsy patients with undetectable (<20 pg/mL), low (20-110 pg/mL) and normal (>110 pg/mL) cerebrospinal fluid (CSF) hypocretin-1 levels. PATIENTS/METHODS: A total of 109 narcolepsy patients and 37 controls were studied; all had available CSF hypocretin-1 measurements. The sleep laboratory studies were conducted between 2008 and 2014. The study retrospectively examined measurements of sleep stage transitions in diurnal and nocturnal continuous polysomnography...
June 2017: Sleep Medicine
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