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https://www.readbyqxmd.com/read/27902931/human-presynaptic-receptors
#1
REVIEW
Eberhard Schlicker, Thomas Feuerstein
Presynaptic receptors are sites at which transmitters, locally formed mediators or hormones inhibit or facilitate the release of a given transmitter from its axon terminals. The interest in the identification of presynaptic receptors has faded in recent years and it may therefore be justified to give an overview of their occurrence in the autonomic and central nervous system; this review will focus on presynaptic receptors in human tissues. Autoreceptors are presynaptic receptors at which a given transmitter restrains its further release, though in some instances may also increase its release...
November 27, 2016: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27865546/french-consensus-management-of-patients-with-hypersomnia-which-strategy
#2
R Lopez, I Arnulf, X Drouot, M Lecendreux, Y Dauvilliers
Central hypersomnias principally involves type 1 narcolepsy (NT1), type 2 narcolepsy (NT2) and idiopathic hypersomnia (IH). Despite great progress made in understanding the physiopathology of NT1 with low cerebrospinal fluid hypocretin-1 levels, current treatment remains symptomatic. The same applies to NT2 and IH, for which the physiopathology is still largely unknown. Controlling excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed night-time sleep are key therapeutic targets in NT1...
November 16, 2016: Revue Neurologique
https://www.readbyqxmd.com/read/27853355/anticonvulsant-effects-of-isomeric-nonimidazole-histamine-h3-receptor-antagonists
#3
Bassem Sadek, Ali Saad, Johannes Stephan Schwed, Lilia Weizel, Miriam Walter, Holger Stark
Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1)...
2016: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/27787717/role-of-the-histamine-h3-receptor-in-the-central-nervous-system
#4
Eberhard Schlicker, Markus Kathmann
The Gi/o protein-coupled histamine H3 receptor is distributed throughout the central nervous system including areas like cerebral cortex, hippocampus and striatum with the density being highest in the posterior hypothalamus, i.e. the area in which the histaminergic cell bodies are located. In contrast to the other histamine receptor subtypes (H1, H2 and H4), the H3 receptor is located presynaptically and shows a constitutive activity. In detail, H3 receptors are involved in the inhibition of histamine release (presynaptic autoreceptor), impulse flow along the histaminergic neurones (somadendritic autoreceptor) and histamine synthesis...
October 28, 2016: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/27568835/action-of-pitolisant-on-the-stimulant-and-rewarding-effects-of-cocaine-in-mice
#5
Christian Brabant, Yana Charlier, Maria Elisa Serrano Navacerrada, Livia Alleva, Ezio Tirelli
Previous studies have demonstrated that the histamine H3 receptor inverse agonist thioperamide potentiates the stimulant and rewarding effects of cocaine. However, these potentiating effects of thioperamide do not necessarily result from H3 receptor blockade since thioperamide is an imidazole-based compound capable of enhancing plasma cocaine concentrations by blocking cytochrome P450 activity. In contrast, Pitolisant is a non-imidazole H3 receptor inverse agonist that has already been tested in clinical trials but it remains to be determined whether this compound also potentiates the behavioral effects of cocaine...
August 26, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27568232/the-dual-acting-ache-inhibitor-and-h3-receptor-antagonist-uw-md-72-reverses-amnesia-induced-by-scopolamine-or-dizocilpine-in-passive-avoidance-paradigm-in-rats
#6
Bassem Sadek, Nadia Khan, Fouad H Darras, Steffen Pockes, Michael Decker
Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5...
October 15, 2016: Physiology & Behavior
https://www.readbyqxmd.com/read/27549768/management-of-narcolepsy
#7
REVIEW
Lucie Barateau, Régis Lopez, Yves Dauvilliers
Narcolepsy type 1 (NT1) and type 2 (NT2) are two rare neurological diseases, classified as central disorders of hypersomnolence. The pathophysiology of NT1 is well known; it is caused by the selective destruction of hypocretin (Hcrt) neurons, by a highly suspected autoimmune process. On the contrary, little is known about NT2 etiology, sharing with NT1 somnolence and signs of dysregulation of rapid eye movement (REM) sleep, but not cataplexy. Management strategies are rather codified, at least in adults, with a lifelong treatment required in NT1, whereas no pharmacological study focused only on NT2 patients, with sometimes spontaneous improvement or disappearance of their symptoms...
October 2016: Current Treatment Options in Neurology
https://www.readbyqxmd.com/read/27538329/-management-of-central-hypersomnias
#8
Yves Dauvilliers, Régis Lopez
Central hypersomnias include narcolepsy type 1, type 2 and idiopathic hypersomnia with daytime sleepiness excessive in the foreground of the clinical symptoms. Despite major advances in our understanding of the mechanisms of the narcolepsy type 1 with a low level of hypocretin-1 in cerebrospinal fluid, its current management is only symptomatic. The current management is also only symptomatic for type 2 narcolepsy and idiopathic hypersomnia with an unknown pathophysiology. Treatment options may vary from a single drug targeting several symptoms or several drugs treating a specific symptom...
June 2016: La Revue du Praticien
https://www.readbyqxmd.com/read/27438291/pitolisant-first-global-approval
#9
Yahiya Y Syed
Pitolisant (Wakix™) is an inverse agonist of the histamine H3 receptor that is being developed by Bioproject. Oral pitolisant is approved in the EU for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant has received a Temporary Authorization of Use in France for this indication in case of treatment failure, intolerance or contraindication to currently available treatment. Pitolisant has orphan drug designation in the EU and the USA. In the pivotal HARMONY I trial, pitolisant significantly decreased excessive daytime sleepiness versus placebo in adults with narcolepsy with or without cataplexy (primary endpoint)...
September 2016: Drugs
https://www.readbyqxmd.com/read/27363923/histamine-h3-receptor-as-a-potential-target-for-cognitive-symptoms-in-neuropsychiatric-diseases
#10
REVIEW
Bassem Sadek, Ali Saad, Adel Sadeq, Fakhreya Jalal, Holger Stark
The potential contributions of the brain histaminergic system in neurodegenerative diseases, and the possiblity of histamine-targeting treatments is attracting considerable interests. The histamine H3 receptor (H3R) is expressed mainly in the central nervous system, and is, consequently, an attractive pharmacological target. Although recently described clinical trials have been disappointing in attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCH), numerous H3R antagonists, including pitolisant, demonstrate potential in the treatment of narcolepsy, excessive daytime sleepiness associated with cognitive impairment, epilepsy, and Alzheimer's disease (AD)...
October 1, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/27303254/multiple-targeting-approaches-on-histamine-h3-receptor-antagonists
#11
REVIEW
Mohammad A Khanfar, Anna Affini, Kiril Lutsenko, Katarina Nikolic, Stefania Butini, Holger Stark
With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27223666/exploratory-phase-ii-trial-to-evaluate-the-safety-and-the-antiepileptic-effect-of-pitolisant-bf2-649-in-refractory-partial-seizures-given-as-adjunctive-treatment-during-3-months
#12
Pierre Collart Dutilleul, Philippe Ryvlin, Philippe Kahane, Laurent Vercueil, Franck Semah, Arnaud Biraben, Jean-Charles Schwartz, Jérôme De Seze, Edouard Hirsch, Nicolas Collongues
BACKGROUND: Pitolisant (BF2.649) is a nonimidazole histamine 3 receptor antagonist. In previous animal studies, it has been shown that pitolisant might be helpful in chronic seizure treatment of both partial and generalized epilepsies. The present study is a multicenter, national, pragmatic, noncomparative, open-label, exploratory phase II trial. It is the first reported study of the clinical effects of pitolisant in human epilepsy. OBJECTIVE: The goal of this trial was to explore the antiepileptic effect of 3 different doses of pitolisant (20, 30, and 40 mg once daily) in patients presenting partial seizure onset despite therapy with adequate dose of 1 to 3 appropriate antiepileptic drugs...
July 2016: Clinical Neuropharmacology
https://www.readbyqxmd.com/read/27216278/h3-histamine-receptor-antagonist-pitolisant-reverses-some-subchronic-disturbances-induced-by-olanzapine-in-mice
#13
Magdalena Dudek, Kamil Kuder, Marcin Kołaczkowski, Adrian Olczyk, Elżbieta Żmudzka, Aleksandra Rak, Marek Bednarski, Karolina Pytka, Jacek Sapa, Katarzyna Kieć-Kononowicz
The use of atypical antipsychotic drugs like olanzapine is associated with side effects such as sedation and depression-like symptoms, especially during the initial period of the use. It is believed that the occurrence of these undesirable effectsis mainly the result of the histamine H1receptors blockade by olanzapine. In addition, use of olanzapine increases the level of triglycerides in the blood, which correlates with growing obesity. The aim of this study was to investigate the influence of pitolisant - H3 histamine antagonist - on subchronic olanzapine-induced depresion-like symptoms, sedation and hypertriglicerydemia...
October 2016: Metabolic Brain Disease
https://www.readbyqxmd.com/read/27155860/treatment-options-for-narcolepsy
#14
Lucie Barateau, Régis Lopez, Yves Dauvilliers
Narcolepsy type 1 and narcolepsy type 2 are central disorders of hypersomnolence. Narcolepsy type 1 is characterized by excessive daytime sleepiness and cataplexy and is associated with hypocretin-1 deficiency. On the other hand, in narcolepsy type 2, cerebrospinal fluid hypocretin-1 levels are normal and cataplexy absent. Despite major advances in our understanding of narcolepsy mechanisms, its current management is only symptomatic. Treatment options may vary from a single drug that targets several symptoms, or multiple medications that each treats a specific symptom...
May 2016: CNS Drugs
https://www.readbyqxmd.com/read/26939881/in-vitro-study-of-histamine-and-histamine-receptor-ligands-influence-on-the-adhesion-of-purified-human-eosinophils-to-endothelium
#15
Marek Grosicki, Tomasz Wójcik, Stefan Chlopicki, Katarzyna Kieć-Kononowicz
It is a well-known fact that histamine is involved in eosinophil-dependent inflammatory responses including cellular chemotaxis and migration. Nevertheless, the relative role of histamine receptors in the mechanisms of eosinophils adhesion to endothelial cells is not known. Therefore the aim of presented study was to examine the effect of selective histamine receptors ligands on eosinophils adhesion to endothelium. For that purpose the highly purified human eosinophils have been isolated from the peripheral blood...
April 15, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/26879827/can-an-early-phase-clinical-pharmacology-study-replace-a-thorough-qt-study-experience-with-a-novel-h3-receptor-antagonist-inverse-agonist
#16
Rashmi R Shah, Pierre Maison-Blanche, Philippe Robert, Emmanuel Denis, Thierry Duvauchelle
OBJECTIVE: The objective of the present study was to compare the effects of pitolisant on QTcF interval in a single ascending dose (SAD) study and a thorough QT (TQT) study. METHODS: The SAD study at three dose levels of pitolisant enrolled 24 males and the TQT study at two dose levels 25 males. Both studies intensively monitored ECGs and pitolisant exposure. Effect on QTcF interval was analysed by Intersection Union Test (IUT) and by exposure-response (ER) analysis...
May 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/26689774/do-traditional-anti-seizure-drugs-have-a-future-a-review-of-potential-anti-seizure-drugs-in-clinical-development
#17
REVIEW
Gaetano Zaccara, Dieter Schmidt
Currently information is available for 20 potential anti-seizure drugs in clinical development. They include candidates with mechanisms of action similar to those of marketed AEDs (allopregnanolone, brivaracetam, ganaxolone, ICA-105665, NS1209, selurampanel); those with new mechanisms of action (beprodon, VX-765); compounds repurposed for the treatment of epilepsy (biperiden, bumetanide, fenfluramine, melatonin, nalutozan, pitolisant, quinidine, valnoctamide, verapamil); and finally candidates with currently unknown mechanisms of action (JNJ-26489112, UCB0942, YKP3089 (Cenobamate)...
February 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/26558298/emerging-drugs-for-common-conditions-of-sleepiness-obstructive-sleep-apnea-and-narcolepsy
#18
REVIEW
Shannon S Sullivan, Christian Guilleminault
INTRODUCTION: Obstructive sleep apnea (OSA) and narcolepsy are sleep disorders associated with high prevalence and high symptomatic burden including prominent sleepiness, daytime dysfunction and poor nocturnal sleep. Both have elevated risk of poor health outcomes. Current therapies are often underutilized, cumbersome, costly or associated with residual symptoms. AREAS COVERED: This review covers current available therapies for OSA and narcolepsy as well as discusses areas for potential drug development, and agents in the therapeutic pipeline, including the cannabinoid dronabinol (OSA), the histamine inverse agonist/ antagonist pitolisant (narcolepsy), and stimulants with uncertain and/or multiple activities such as JZP-110 and JZP-386 (narcolepsy, possibly OSA)...
2015: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/26467607/the-dual-acting-h3-receptor-antagonist-and-ache-inhibitor-uw-md-71-dose-dependently-enhances-memory-retrieval-and-reverses-dizocilpine-induced-memory-impairment-in-rats
#19
Nadia Khan, Ali Saad, Syed M Nurulain, Fouad H Darras, Michael Decker, Bassem Sadek
Both the histamine H3 receptor (H3R) and acetylcholine esterase (AChE) are involved in the regulation of release and metabolism of acetylcholine and several other central neurotransmitters. Therefore, dual-active H3R antagonists and AChE inhibitors (AChEIs) have shown in several studies to hold promise to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting H3R antagonist and AChEI 7-(3-(piperidin-1-yl)propoxy)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline (UW-MD-71) with excellent selectivity profiles over both the three other HRs as well as the AChE's isoenzyme butyrylcholinesterase (BChE) shows high and balanced in vitro affinities at both H3R and AChE with IC50 of 33...
January 15, 2016: Behavioural Brain Research
https://www.readbyqxmd.com/read/26282120/histamine-and-histamine-receptors-in-tourette-syndrome-and-other-neuropsychiatric-conditions
#20
REVIEW
Maximiliano Rapanelli, Christopher Pittenger
The potential contributions of dysregulation of the brain's histaminergic modulatory system to neuropsychiatric disease, and the potential of histamine-targeting medications as therapeutic agents, are gradually coming into focus. The H3R receptor, which is expressed primarily in the central nervous system, is a promising pharmacotherapeutic target. Recent evidence for a contribution of histamine dysregulation to Tourette syndrome and tic disorders is particularly strong; although specific mutations in histamine-associated genes are rare, they have led to informative studies in animal models that may pave the way for therapeutic advances...
July 2016: Neuropharmacology
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