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Biomedical subjects

Yves Dauvilliers

Publications and source records attributed to Yves Dauvilliers.

At least 19 recordsLinked to original sources
PubMed2026

Safety, tolerability, and efficacy of alixorexton, a selective orexin 2 receptor agonist for narcolepsy type 1 (Vibrance-1): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: The clinical potential of orexin 2 receptor (OX2R) agonism for improving measures of wakefulness and cataplexy in patients with narcolepsy type 1 has been described in a phase 2 study. Here, we aimed to evaluate the safety, tolerability, and efficacy of alixorexton, another oral OX2R agonist, in narcolepsy type 1. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, adult participants (aged 18-70 years) with narcolepsy type 1 were recruited from 46 hospitals and private research centres across the USA, Europe, and Australia. Participants were centrally randomly assigned (1:1:1:1) in blocks of four via an interactive response technology system stratified by region and baseline weekly cataplexy rate (WCR) to receive 4 mg, 6 mg, or 8 mg tablets of alixorexton or placebo once daily for 6 weeks, followed by an optional 7-week open-label extension. Participants had narcolepsy type 1, diagnosed per the International Classification of Sleep Disorders, Third Edition, and confirmed by overnight polysomnography and the Multiple Sleep Latency Test or cerebrospinal hypocretin-1 concentrations. The sponsor, assessors, investigators, and participants were masked during the randomised double-blind treatment period. Efficacy and safety assessments were conducted in participants who received at least one dose of study drug. The primary endpoint was change from baseline to week 6 in mean sleep latency (MSL) on the Maintenance of Wakefulness Test (MWT). Safety endpoints included treatment-emergent adverse events. This trial was registered with ClinicalTrials.gov (NCT06358950) and is completed. FINDINGS: Between May 24, 2024, and May 5, 2025, 153 individuals were screened and 92 participants were randomly assigned to receive alixorexton 4 mg (n=23), 6 mg (n=22), 8 mg (n=24), or placebo (n=23). Mean age was 33&#xb7;5 years (SD 12&#xb7;1), 57 (62%) were women, and 35 (38%) were men. At week 6, the observed MSL on the MWT was 2&#xb7;3 min (SD 2&#xb7;7) for placebo, 24&#xb7;0 min (8&#xb7;7) for alixorexton 4 mg, 25&#xb7;9 min (9&#xb7;4) for 6 mg, and 28&#xb7;2 min (11&#xb7;4) for 8 mg. Alixorexton improved MSL on the MWT, with a least-squares mean placebo-corrected change from baseline of 22&#xb7;2 min (95% CI 17&#xb7;2-27&#xb7;2) for alixorexton 4 mg, 24&#xb7;1 min (19&#xb7;0-29&#xb7;1) for 6 mg, and 26&#xb7;0 min (21&#xb7;0-31&#xb7;0) for 8 mg (adjusted p=0&#xb7;0099 for 4 mg, adjusted p<0&#xb7;0001 for 6 mg and 8 mg). Treatment-emergent adverse events occurring in at least 5% of participants given alixorexton and more frequently than those given placebo up to week 6 were pollakiuria (38 [55%]), insomnia (19 [28%]), salivary hypersecretion (17 [25%]), micturition urgency (ten [14%]), blurred vision (ten [14%]), and hyperhidrosis (five [7%]). INTERPRETATION: In this phase 2 trial, once-daily oral alixorexton provided clinically meaningful improvements at 6 weeks for participants with narcolepsy type 1, including in wakefulness, excessive daytime sleepiness, and cataplexy. The treatment was generally well tolerated, with adverse events consistent with the known on-target effects of OX2R agonists. Together, these findings support the further phase 3 evaluation of alixorexton as a potential therapeutic option for people with narcolepsy type 1. FUNDING: Alkermes.

Humans↗
PubMed2025

Post-traumatic stress disorder and REM-sleep behavior disorder: exploring genetic associations and causal links.

OBJECTIVE: To explore potential genetic and/or causal associations between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder. METHODS: We conducted polygenic risk score, genetic correlation, and Mendelian randomization analyses using the latest genome-wide association studies summary statistics and individual genotyping data. Next, a blinded observer examined dopamine transporter imaging binding status-a marker of neurodegeneration-in patients with isolated/idiopathic rapid-eye movement sleep behavior disorder, with (N = 6) and without Post-Traumatic Stress Disorder (N = 32). RESULTS: Polygenic risk scores for Post-Traumatic Stress Disorder were associated with isolated/idiopathic rapid-eye-movement sleep behavior disorder, with each standard deviation increase linked to 14.7% higher odds (odds ratio = 1.15, 95% confidence interval: 1.04 to 1.26, p = 0.005). However, genetic correlation was weak, and Mendelian randomization did not support a potential causal relationship. The proportion of individuals with abnormal dopamine transporter imaging binding status was significantly higher in the Post-Traumatic Stress Disorder group compared to those without the disorder (p=0.01, X2 = 6.62). INTERPRETATION: Polygenic risk scores analysis identified an association between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder, consistent with the result from the small exploratory substudy. The lack of strong genetic correlation or causation may reflect limited sample size. Further research with larger and more diverse cohorts is crucial to clarify the genetic, biological and physiological mechanisms underlying this association.

Journal Article↗
PubMed2006

Kleine-Levin syndrome in a 14-year-old girl: CSF hypocretin-1 measurements.

CSF hypocretin-1 measurements were performed during a period of hypersomnia and during an asymptomatic interval in a 14-year-old girl affected with severe Kleine-Levin syndrome. A twofold decrease in hypocretin-1 was evidenced during the period of hypersomnia in comparison with the asymptomatic interval. Together with previous data, this result is in favour of recurrent dysfunction at the hypothalamic level in Kleine-Levin syndrome.

Adolescent↗
PubMed2006

Differential diagnosis in hypersomnia.

Hypersomnia includes a group of disorders in which the primary complaint is excessive daytime sleepiness. Chronic hypersomnia is characterized by at least 3 months of excessive sleepiness prior to diagnosis and may affect 4% to 6% of the population. The severity of daytime sleepiness needs to be quantified by subjective scales (at least the Epworth sleepiness scale) and objective tests such as the multiple sleep latency test. Chronic hypersomnia does not correspond to an individual clinical entity but includes numerous different etiologies of hypersomnia as recently reported in the revised International Classification of Sleep Disorders. This review details most of those disorders, including narcolepsy with and without cataplexy, idiopathic hypersomnia with and without long sleep time, recurrent hypersomnia, behaviorally induced insufficient sleep syndrome, hypersomnia due to medical condition, hypersomnia due to drug or substance, hypersomnia not due to a substance or known physiologic condition, and also sleep-related disordered breathing and periodic leg movement disorders.

Chronic Disease↗
PubMed2006

Molecular genetics and treatment of narcolepsy.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.

Animals↗
PubMed2005

Retinoic acid signaling affects cortical synchrony during sleep.

Delta oscillations, characteristic of the electroencephalogram (EEG) of slow wave sleep, estimate sleep depth and need and are thought to be closely linked to the recovery function of sleep. The cellular mechanisms underlying the generation of delta waves at the cortical and thalamic levels are well documented, but the molecular regulatory mechanisms remain elusive. Here we demonstrate in the mouse that the gene encoding the retinoic acid receptor beta determines the contribution of delta oscillations to the sleep EEG. Thus, retinoic acid signaling, which is involved in the patterning of the brain and dopaminergic pathways, regulates cortical synchrony in the adult.

Animals↗
PubMed2005

No effect on cognitive function from daily mobile phone use.

The increasing use of mobiles phones (MP) has raised the problem of the effects of daily electromagnetic fields (EMF) exposure on human health. To date several studies have been published concerning the effects of acute MP exposure on psychomotor performances. This study investigated the effects of daily exposure to GSM 900 type MP on cognitive function. Fifty-five subjects (27 male and 28 female) were divided into two groups: a group with MP switched on and a group with MP switched off. The two groups were matched according to age, gender, and IQ. This double blind study lasted for 45 days and was divided in three periods: baseline (BLP, 2 days), exposure (EP, 27 days), and recovery (RP, 13 days). Subjects were exposed during EP and sham exposed during RP for 2 h/day, 5 days/week. The neuropsychological test battery composed of 22 tasks screened four neuropsychological categories: information processing, attention capacity, memory function, and executive function. This neuropsychological battery was performed four times on day 2 (BLP), day 15 (EP), day 29 (EP), and day 43 (RP). Our results indicate that daily MP use has no effect on cognitive function after a 13-h rest period.

Adolescent↗
PubMed2005

Family studies in insomnia.

OBJECTIVE: Several predisposing factors to insomnia have been hypothesized, including a familial component; however, few studies have focused on this topic. The aim of this study is to evaluate the prevalence of insomnia among first-degree relatives of chronic insomniacs and to compare the symptoms between sporadic and familial insomnia. METHODS: Two hundred fifty-six consecutive chronic insomniacs completed a clinical interview, psychometric questionnaires, a questionnaire on the family history of insomnia and, when indicated, a polysomnography. A control group was performed to estimate a base-rate incidence of insomnia in their families. RESULTS: Patients with primary (n=77) and psychiatric (n=104) insomnia were definitely included. Of those with primary insomnia, 72.7% reported familial insomnia compared with 24.1% in the noninsomnia control group. Among the psychiatric insomniacs, 43.3% reported familial insomnia. The mother was the relative most frequently affected. Comparisons between the family prevalence rates of insomnia assessed by the probands and by first-degree relatives show high concordance. A tendency to a younger age at onset was observed in familial and primary insomnia. CONCLUSION: This study reports a significant increase of familial aggregation of insomnia, warranting further genetic studies in primary insomnia with early age at onset.

Adolescent↗
PubMed2005

Genes for normal sleep and sleep disorders.

Sleep and wakefulness are complex behaviors that are influenced by many genetic and environmental factors, which are beginning to be discovered. The contribution of genetic components to sleep disorders is also increasingly recognized as important. Point mutations in the prion protein, period 2, and the prepro-hypocretin/orexin gene have been found as the cause of a few sleep disorders but the possibility that other gene defects may contribute to the pathophysiology of major sleep disorders is worth in-depth investigations. However, single gene disorders are rare and most common disorders are complex in terms of their genetic susceptibility, environmental effects, gene-gene, and gene-environment interactions. We review here the current progress in the genetics of normal and pathological sleep.

Circadian Rhythm↗
PubMed2005

Hypersomnia.

Hypersomnia, a complaint of excessive daytime sleep or sleepiness, affects 4% to 6% of the population, with an impact on the everyday life of the patient Methodological tools to explore sleep and wakefulness (interview, questionnaires, sleep diary, polysomnography, Multiple Sleep Latency Test, Maintenance of Wakefulness Test) and psychomotor tests (for example, psychomotor vigilance task and Oxford Sleep Resistance or Osler Test) help distinguish between the causes of hypersomnia. In this article, the causes of hypersomnia are detailed following the conventional classification of hypersomnic syndromes: narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, insufficient sleep syndrome, medication- and toxin-dependent sleepiness, hypersomnia associated with psychiatric disorders, hypersomnia associated with neurological disorders, posttraumatic hypersomnia, infection (with a special emphasis on the differences between bacterial and viral diseases compared with parasitic diseases, such as sleeping sickness) and hypersomnia, hypersomnia associated with metabolic or endocrine diseases, breathing-related sleep disorders and sleep apnea syndromes, and periodic limb movements in sleep.

Circadian Rhythm↗
PubMed2004

[Narcolepsy, from Westphal to hypocretin].

CLINICAL DATA: Narcolepsy is a poorly known disease, though not exceptional, with a prevalence of 25 to 35 per 100,000 according to various surveys. Its onset can be anytime from childhood to the fifties with a peak in the second decade. It is characterized by two cardinal symptoms, irresistible sleep episodes and cataplexy or sudden loss of muscle tone triggered by emotional situations. The other symptoms, referred to as accessory due to their inconstancy, are hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. Its diagnosis relies on the identification of the cardinal symptoms. Laboratory tests are required to confirm the diagnosis before initiation of a life-long treatment. Theses test include: all-night and daytime polysomnography documenting sleep-onset REM periods, HLA typing, showing the association with HLA DQB1*0602, and, in unclear cases only, measurement of cerebro-spinal fluid (CSF) hypocretine-1 showing values below 110pg/ml, highly specific of narcolepsy with cataplexy. Pathophysiology owes a lot to the existence of a natural canine model, the narcoleptic dog. Irresistible sleep episodes and cataplexy exhibit different pharmacological control, the former depending on dopaminergic systems and the latter on noradrenergic systems. The most remarkable findings of the last twenty years are the close association with HLA DQB1*0602, the identification of a mutation of hypocretin receptor 2 in the narcoleptic dog and the absence of CSF hypocretin-1 in 90% of patients. An autoimmune mechanism is suggested but not evidenced. THREE-FOLD TREATMENT: First line treatment of irresistible sleep episodes in modafinil, Cataplexy or tricyclic antidepressants or sodium oxybate, and disturbed nocturnal sleep by hypnotics or sodium oxybate. Current therapeutic research is oriented towards hypocretin agonists and immunosuppressors.

Animals↗
PubMed2004

Normal CSF hypocretin-1 (orexin A) levels in dementia with Lewy bodies associated with excessive daytime sleepiness.

Excessive daytime sleepiness, hallucinations and REM sleep behavior disorder are symptoms reported in both dementia with Lewy bodies (DLB) and narcolepsy. Considering the demonstration of low hypocretin-1/orexin A levels in the cerebrospinal fluid (CSF) of most patients with narcolepsy, we hypothesized the presence of a deficient hypocretinergic transmission in DLB. Hypocretin-1 was tested in the CSF of 10 DLB patients. Levels were found to be in the normal range (mean 521 pg/ml, range 382-667) when compared to controls (n = 20, mean 497 pg/ml, range 350-603) and Alzheimer's disease patients (n = 7, mean 474 pg/ml, range 333-564). In DLB, excessive daytime sleepiness, hallucinations and REM sleep behavior may occur in the absence of a detectable hypocretin deficiency.

Aged↗
PubMed2004

A narcolepsy susceptibility locus maps to a 5 Mb region of chromosome 21q.

The genetic basis of human narcolepsy remains poorly understood. Multiplex families with full-blown narcolepsy-cataplexy are rare, whereas families with both narcolepsy-cataplexy and excessive daytime sleepiness without cataplexy are more common. We performed a genomewide linkage analysis in a large French family with four members affected with narcolepsy-cataplexy and 10 others with isolated recurrent naps or lapses into sleep. Only three regions showed logarithm of odds (LOD) scores greater than 1 in two-point linkage analysis (D6S1960, D11S2359, and D21S228). Genotyping additional markers provided support for linkage to 9 markers on chromosome 21 (maximum two-point LOD score, 3.36 at D21S1245). The multipoint linkage analysis using SimWalk2 provided further evidence for linkage to the same region (maximum parametric LOD score, 4.00 at 21GT26K). A single haplotype was shared by all affected individuals and informative crossovers indicated that the elusive gene that confers susceptibility to narcolepsy is likely to be located between markers D21S267 and ABCG1, in a 5.15 Mb region of 21q.

Child↗
PubMed2004

Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset.

Hypocretin/orexin deficiency appears to be a consistent feature of narcolepsy with a putative autoimmune mechanism involved. We treated four hypocretin/orexin-deficient narcolepsy patients with intravenous immunoglobulins and assessed the efficacy by repeated polysomnographies and questionnaires. Three patients received the treatment within a few months after acute onset of narcolepsy. A clear improvement in the frequency and severity of cataplexy was obtained with a benefic effect up to 7 months without any anticataplectics drugs at follow-up. Our findings point to the importance of early diagnosis of narcolepsy, which once treated quickly may modify its long-term outlook.

Adult↗
PubMed2004

Effect of cognitive behavioural therapy for insomnia on sleep architecture and sleep EEG power spectra in psychophysiological insomnia.

There is now an overwhelming preponderance of evidence that cognitive behavioural therapy for insomnia (CBT-I) is effective, as effective as sedative hypnotics during acute treatment (4-8 weeks), and is more effective in long term (following treatment). Although the efficacy of CBT-I in the treatment of chronic insomnia is well known, however there is little objective data on the effects of CBT-I on sleep architecture and sleep EEG power densities. The present study evaluated, first, subjective change in sleep quality and quantity, and secondly the modifications occurring in polysomnography and EEG power densities during sleep after 8 weeks of CBT-I. Nine free drug patients with psychophysiological insomnia, aged 33-62 years (mean age 47 +/- 9.7 years), seven female and two male participated in the study. Self-report questionnaires were administered 1 week before and 1 week after CBT-I, a sleep diary was completed each day 1 week before CBT-I, during CBT-I and 1 week after CBT-I. Subjects underwent two consecutive polysomnographic nights before and after CBT-I. Spectral analysis was performed the second night following 16 h of controlled wakefulness. After CBT-I, only scales assessing insomnia were significantly decreased, stages 2, REM sleep and SWS durations were significantly increased. Slow wave activity (SWA) was increased and the SWA decay shortened, beta and sigma activity were reduced. In conclusion CBT-I improves both subjective and objective sleep quality of sleep. CBT-I may enhance sleep pressure and improve homeostatic sleep regulation.

Adult↗
PubMed2003

Aerobic determinants of the decline in preferred walking speed in healthy, active 65- and 80-year-olds.

The preferred walking speed is a common measure of mobility that declines with age and has been related to maximal oxygen uptake (VO(2,max)). The present study determined whether this decline is associated with a higher percentage of the ventilatory threshold in older adults walking at their preferred speed. We compared the preferred walking speed and VO2 at this speed in relation to both VO(2,max) and VO2 corresponding to the ventilatory threshold (TVE) in healthy, physically active sexagenarians (G65, n=10) and octogenarians (G80, n=10) walking on a treadmill. The preferred walking speed was lower in G80 (1.16+/-0.09 m.s(-1)) than in G65 (1.38+/-0.09 m.s(-1); P<0.001). Energy expenditure and the energy cost of walking at the preferred walking speed were not significantly different between the two groups. G80 subjects exhibited significantly higher fractions of VO(2,max) (60.8+/-8.0%) and TVE (74.2+/-7.9%) at the preferred walking speed than G65 (42.9+/-5.0 and 53.2+/-5.7% respectively; P<0.001). Multiple regression analysis showed that the fraction of TVE was the main determinant, with a small contribution of height, in the decline in the preferred walking speed in healthy and active elderly subjects (R2=64%; P<0.001). These findings show that with age, walking at the preferred speed requires a higher fraction of TVE. This increase in the relative physiological effort at preferred walking speed could explain the reduction in this gait speed in healthy older subjects.

Aged↗