Pitolisant versus placebo or modafinil in patients with narcolepsy : a double-blind, randomised trial
TL;DR: Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil, and could offer a new treatment option for patients with narcolepsy.
Abstract: Summary Background Narcolepsy is characterised by excessive daytime sleepiness (EDS) and cataplexy. Histamine neurons are crucial to maintain wakefulness. We assessed the safety and efficacy of pitolisant (previously called BF2.649), a selective histamine H3 receptor inverse agonist that activates these neurons, in patients with narcolepsy. Methods For this double-blind, randomised, parallel-group controlled trial, we recruited patients with narcolepsy from 32 sleep disorder centres in five European countries. Patients were eligible if they were aged 18 years or older, had not taken psychostimulants for at least 14 days, and had EDS (defined as an Epworth Sleepiness Scale [ESS] score of at least 14). Using a computer-generated randomisation sequence, we randomly allocated patients to receive pitolisant, modafinil, or placebo (1:1:1). Treatment lasted 8 weeks: 3 weeks of flexible dosing according to investigator's judgment (10 mg, 20 mg, or 40 mg a day of pitolisant; 100 mg, 200 mg or 400 mg a day of modafinil) followed by 5 weeks of stable dosing. Patients took four tablets a day in a double-dummy design to ensure masking. For the primary analysis, assessed in the intention-to-treat population, we assessed the superiority of pitolisant versus placebo, and the non-inferiority of pitolisant versus modafinil. This trial is registered with ClinicalTrials.gov, number NCT01067222. Findings Between May 26, 2009, and June 30, 2010, we screened 110 patients, 95 of whom were eligible and randomly assigned to treatment: 30 to placebo, 32 to pitolisant, and 33 to modafinil. Over the 8-week treatment period, mean ESS score reductions were −3·4 (SD 4·2) in the placebo group, −5·8 (6·2) in the pitolisant group, and −6·9 (6·2) in the modafinil group. Our primary analysis of between-group differences in mean ESS score at endpoint (adjusted for baseline) showed pitolisant to be superior to placebo (difference −3·0, 95% CI −5·6 to −0·4; p=0·024), but not non-inferior to modafinil (difference 0·12, 95% CI −2·5 to 2·7; p=0·250). We recorded 22 adverse events with pitolisant, 26 with modafinil, and ten with placebo. Six severe adverse events were treatment-related: one with pitolisant (abdominal discomfort) and five with modafinil (abdominal pain, abnormal behaviour, amphetamine-like withdrawal symptoms, lymphoadenopathy, and inner ear disorders). Interpretation Pitolisant at doses up to 40 mg was efficacious on EDS compared with placebo and well tolerated compared with modafinil. If these findings are substantiated in further studies, pitolisant could offer a new treatment option for patients with narcolepsy. Funding Bioprojet, France.
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TL;DR: The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons, a block of these actions promotes waking and the development of anti-inflammatory drugs is anticipated.
Abstract: Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein–coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated.
411 citations
Cites background or result from "Pitolisant versus placebo or modafi..."
...649, 1-piperidine, hydrochloride, pitolisant, Wakix, 45) (Dauvilliers et al., 2013) having been officially filed for licensing by Bioprojet early in 2014 for use in refractory narcolepsy....
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...Pitolisant was well tolerated (with only one patient displaying a serious side effect, namely abdominal discomfort) compared with the previous gold standard, modafinil, where multiple issues arose (Dauvilliers et al., 2013)....
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University of Bern1, King's College London2, École Polytechnique Fédérale de Lausanne3, Francis Crick Institute4, Peking University5, Leiden University6, University of Copenhagen7, Centre national de la recherche scientifique8, Claude Bernard University Lyon 19, French Institute of Health and Medical Research10, University of Marburg11, University of Tsukuba12, University of Lugano13, ETH Zurich14, Beth Israel Deaconess Medical Center15, University of Lausanne16, University of Montpellier17
TL;DR: Current understanding of how genetic, environmental and immune-related factors contribute to a prominent orexin signalling deficiency in patients with NT1 are focused on, along with uncertainties concerning the ‘narcoleptic borderland’, including narcolepsy type 2 (NT2).
Abstract: Narcolepsy is a rare brain disorder that reflects a selective loss or dysfunction of orexin (also known as hypocretin) neurons of the lateral hypothalamus. Narcolepsy type 1 (NT1) is characterized by excessive daytime sleepiness and cataplexy, accompanied by sleep-wake symptoms, such as hallucinations, sleep paralysis and disturbed sleep. Diagnosis is based on these clinical features and supported by biomarkers: evidence of rapid eye movement sleep periods soon after sleep onset; cerebrospinal fluid orexin deficiency; and positivity for HLA-DQB1*06:02. Symptomatic treatment with stimulant and anticataplectic drugs is usually efficacious. This Review focuses on our current understanding of how genetic, environmental and immune-related factors contribute to a prominent (but not isolated) orexin signalling deficiency in patients with NT1. Data supporting the view of NT1 as a hypothalamic disorder affecting not only sleep-wake but also motor, psychiatric, emotional, cognitive, metabolic and autonomic functions are presented, along with uncertainties concerning the 'narcoleptic borderland', including narcolepsy type 2 (NT2). The limitations of current diagnostic criteria for narcolepsy are discussed, and a possible new classification system incorporating the borderland conditions is presented. Finally, advances and obstacles in the symptomatic and causal treatment of narcolepsy are reviewed.
295 citations
TL;DR: Interest in narcolepsy has increased since the epidemiological observations that H1N1 infection and vaccination are potential triggering factors, and an increase in the incidence after the pandemic AS03 adjuvanted H 1N1 vaccination in 2010 from Sweden and Finland supports the immune-mediated pathogenesis.
Abstract: Summary Narcolepsy is a sleep disorder characterised by loss of hypothalamic hypocretin (orexin) neurons. The prevalence of narcolepsy is about 30 per 100 000 people, and typical age at onset is 12–16 years. Narcolepsy is strongly associated with the HLA-DQB1*06:02 genotype, and has been thought of as an immune-mediated disease. Other risk genes, such as T-cell-receptor α chain and purinergic receptor subtype 2Y11, are also implicated. Interest in narcolepsy has increased since the epidemiological observations that H1N1 infection and vaccination are potential triggering factors, and an increase in the incidence of narcolepsy after the pandemic AS03 adjuvanted H1N1 vaccination in 2010 from Sweden and Finland supports the immune-mediated pathogenesis. Epidemiological observations from studies in China also suggest a role for H1N1 virus infections as a trigger for narcolepsy. Although the pathological mechanisms are unknown, an H1N1 virus-derived antigen might be the trigger.
205 citations
28 Aug 2014
TL;DR: In this paper, an H1N1 virus-derived antigen might be the trigger for narcolepsy, which is a sleep disorder characterized by loss of hypothalamic hypocretin (orexin) neurons and other risk genes such as T-cell-receptor α chain and purinergic receptor subtype 2Y11.
Abstract: Summary Narcolepsy is a sleep disorder characterised by loss of hypothalamic hypocretin (orexin) neurons. The prevalence of narcolepsy is about 30 per 100 000 people, and typical age at onset is 12–16 years. Narcolepsy is strongly associated with the HLA-DQB1*06:02 genotype, and has been thought of as an immune-mediated disease. Other risk genes, such as T-cell-receptor α chain and purinergic receptor subtype 2Y11, are also implicated. Interest in narcolepsy has increased since the epidemiological observations that H1N1 infection and vaccination are potential triggering factors, and an increase in the incidence of narcolepsy after the pandemic AS03 adjuvanted H1N1 vaccination in 2010 from Sweden and Finland supports the immune-mediated pathogenesis. Epidemiological observations from studies in China also suggest a role for H1N1 virus infections as a trigger for narcolepsy. Although the pathological mechanisms are unknown, an H1N1 virus-derived antigen might be the trigger.
196 citations
TL;DR: The characteristics of the H3R are reviewed, namely, its structure, constitutive activity, isoforms, signal transduction pathways, regional differences in expression and localization, selective agonist, antagonists and inverse agonists, dimerization with other neurotransmitter receptors, and the main presynaptic and postsynaptic effects resulting from its activation.
Abstract: Among the four G protein–coupled receptors (H1–H4) identified as mediators of the biologic effects of histamine, the H3 receptor (H3R) is distinguished for its almost exclusive expression in the nervous system and the large variety of isoforms generated by alternative splicing of the corresponding mRNA. Additionally, it exhibits dual functionality as autoreceptor and heteroreceptor, and this enables H3Rs to modulate the histaminergic and other neurotransmitter systems. The cloning of the H3R cDNA in 1999 by Lovenberg et al. allowed for detailed studies of its molecular aspects. In this work, we review the characteristics of the H3R, namely, its structure, constitutive activity, isoforms, signal transduction pathways, regional differences in expression and localization, selective agonists, antagonists and inverse agonists, dimerization with other neurotransmitter receptors, and the main presynaptic and postsynaptic effects resulting from its activation. The H3R has attracted interest as a potential drug target for the treatment of several important neurologic and psychiatric disorders, such as Alzheimer and Parkinson diseases, Gilles de la Tourette syndrome, and addiction.
137 citations
Cites background from "Pitolisant versus placebo or modafi..."
...…is not central to the pathophysiology, H3R antagonists/inverse agonists such as pitolisant are useful for the treatment of excessive sleepiness disorders, namely, narcolepsy and idiopathic hypersomnia, by improving alertness (Lin et al., 2008; Inocente et al., 2012; Dauvilliers et al., 2013)....
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References
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11 Jun 2013
113,134 citations
TL;DR: The development and use of a new scale, the Epworth sleepiness scale (ESS), is described, which is a simple, self-administered questionnaire which is shown to provide a measurement of the subject's general level of daytime sleepiness.
Abstract: The development and use of a new scale, the Epworth sleepiness scale (ESS), is described. This is a simple, self-administered questionnaire which is shown to provide a measurement of the subject's general level of daytime sleepiness. One hundred and eighty adults answered the ESS, including 30 normal men and women as controls and 150 patients with a range of sleep disorders. They rated the chances that they would doze off or fall asleep when in eight different situations commonly encountered in daily life. Total ESS scores significantly distinguished normal subjects from patients in various diagnostic groups including obstructive sleep apnea syndrome, narcolepsy and idiopathic hypersomnia. ESS scores were significantly correlated with sleep latency measured during the multiple sleep latency test and during overnight polysomnography. In patients with obstructive sleep apnea syndrome ESS scores were significantly correlated with the respiratory disturbance index and the minimum SaO2 recorded overnight. ESS scores of patients who simply snored did not differ from controls.
13,788 citations
TL;DR: This outstanding manual is more than an outline; it includes diagnostic criteria, clinical course, predisposing factors, prevalence, differential diagnosis, and a bibliography for each of the numerous disorders.
Abstract: I congratulate the American Sleep Disorders Association for this outstanding manual, modeled after DSM-111 and consistent in style with the ICD-9-CM Classification. Like the DSM-111, it is more than an outline; it includes diagnostic criteria, clinical course, predisposing factors, prevalence, differential diagnosis, and a bibliography for each of the numerous disorders. The book obviously is essential for polysomnographers, but all neurologists seeing patients with sleep disorders or sleep-related phenomena should have i t available.
4,004 citations
3,512 citations
TL;DR: In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined, indicating most cases of human narcolepsy are associated with a deficient hypocretin system.
Abstract: We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.
1,939 citations