BACKGROUND: Lower-sodium oxybate (LXB) is an oxybate medication with the same active moiety as sodium oxybate (SXB) and a unique composition of cations, resulting in 92% less sodium. LXB was shown to improve cataplexy and excessive daytime sleepiness in people with narcolepsy in a placebo-controlled, double-blind, randomized withdrawal study (NCT03030599). Additional analyses of data from this study were conducted to explore the effects of LXB on cataplexy, including the clinical course and feasibility of transition from other anticataplectics to LXB monotherapy. OBJECTIVE: The aim of these analyses was to evaluate cataplexy frequency during initiation/optimization of LXB and taper/discontinuation of prior antidepressant/anticataplectic medications. METHODS: Eligible participants (adults aged 18-70 years with narcolepsy with cataplexy) entered the study taking SXB only (group A), SXB + other anticataplectics (group B), or anticataplectic medication other than SXB (group C), or were cataplexy-treatment naive (group D). LXB was initiated/optimized during a 12-week, open-label, optimized treatment and titration period (OLOTTP). Other anticataplectics were tapered/discontinued during weeks 3-10 of OLOTTP. A 2-week stable-dose period (SDP; during which participants took a stable dose of open-label LXB) and 2-week double-blind randomized withdrawal period (during which participants were randomized to continue LXB treatment or switch to placebo) followed OLOTTP. Treatment-emergent adverse events (TEAEs) were recorded throughout the duration of the study. RESULTS: At the beginning of OLOTTP, median weekly cataplexy attacks were lower in participants taking SXB at study entry (SXB only [2.00]; SXB + other anticataplectics [0.58]) versus participants who were taking other anticataplectics (3.50) or were anticataplectic naive (5.83). Median weekly cataplexy attacks decreased during weeks 1-2 of OLOTTP in all groups. Increased cataplexy frequency was observed in participants tapering/discontinuing other anticataplectics during weeks 3-10 and was more prominent in participants taking other anticataplectics alone compared with those taking SXB plus other anticataplectics. Cataplexy frequency decreased throughout initiation/optimization in anticataplectic-naive participants. Median number of cataplexy-free days/week at the end of SDP (study week 14) was similar in all groups (6.0, 6.1, 6.0, and 6.2 in groups A, B, C, and D, respectively). During OLOTTP and SDP, TEAEs of worsening cataplexy were reported in 0%, 47.8%, 16.7%, and 2.2% of participants in groups A, B, C, and D, respectively; most TEAEs of worsening cataplexy were reported during tapering/discontinuation of other anticataplectics. CONCLUSIONS: LXB monotherapy was effective in reducing cataplexy and increasing cataplexy-free days. These results illustrate the feasibility of switching from SXB to LXB while tapering/discontinuing other anticataplectics. TRIAL REGISTRATION: A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy; https://clinicaltrials.gov/ct2/show/NCT03030599 ; clinicaltrials.gov identifier: NCT03030599.

People with narcolepsy are often sleepy during the day. They may also have sudden muscle weakness (known as cataplexy). Lower-sodium oxybate (LXB) is a narcolepsy medicine that is similar to sodium oxybate (SXB) but has 92% less sodium. A recent study found that treatment with LXB was better at reducing how often people with narcolepsy had sleepiness and cataplexy than no medicine at all (NCT03030599). This paper is about the first 12 weeks of that study, when all the people taking part in the study first tried LXB to check that they were being given the right amount. In people who only took LXB, cataplexy happened less often over time. Some people were already taking other medicines to treat their cataplexy (such as antidepressants), so they were asked to slowly stop those medicines while taking LXB. In those people, cataplexy happened more often at first as they stopped taking antidepressants and then less often later on. The increase in cataplexy when antidepressants were stopped was smaller in people who switched from SXB to LXB. This study shows that many people getting treatment for narcolepsy can switch to LXB without their cataplexy becoming worse.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• kataplexie * farmakoterapie   MeSH
• lidé MeSH
• narkolepsie * chemicky indukované   farmakoterapie   MeSH
• oxybát sodný * škodlivé účinky   MeSH
• poruchy nadměrné spavosti * farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• oxybát sodný * MeSH

STUDY OBJECTIVES: Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB). METHODS: Adults aged 18-70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment. RESULTS: Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (-0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (-1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%). CONCLUSIONS: Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB. CLINICAL TRIAL REGISTRATION: NCT03030599.

• Klíčová slova
• JZP-258, cataplexy, excessive daytime sleepiness, narcolepsy, sodium oxybate,
• MeSH
• dospělí MeSH
• draslík MeSH
• dvojitá slepá metoda MeSH
• hořčík MeSH
• kataplexie * farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• narkolepsie * farmakoterapie   MeSH
• oxybát sodný * škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• sodík MeSH
• vápník MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• draslík MeSH
• hořčík MeSH
• oxybát sodný * MeSH
• sodík MeSH
• vápník MeSH

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. A linear regression analysis with multivariate models was used with stepwise variable selection. RESULTS: In narcolepsy patients, maximal oxygen uptake (VO2peak) was 30.1 ± 7.5 mL/kg/min, which was lower than 36.0 ± 7.8 mL/kg/min, p = 0.001, in controls and corresponded to 86.4% ± 20.0% of the population norm (VO2peak%) and to a standard deviation (VO2peakSD) of -1.08 ± 1.63 mL/kg/min of the population norm. VO2peak depended primarily on gender (p = 0.007) and on sleepiness (p = 0.046). VO2peak% depended on sleepiness (p = 0.028) and on age (p = 0.039). VO2peakSD depended on the number of cataplexy episodes per month (p = 0.015) and on age (p = 0.030). CONCLUSIONS: Cardiopulmonary fitness in narcolepsy and in narcolepsy without cataplexy is inversely related to the degree of sleepiness and cataplexy episode frequency.

• Klíčová slova
• Cardiopulmonary fitness, Exercise stress test, Influence of disease severity, Narcolepsy with cataplexy, Narcolepsy without cataplexy,
• MeSH
• akcelerometrie MeSH
• bdění fyziologie   MeSH
• cvičení fyziologie   MeSH
• dospělí MeSH
• kataplexie komplikace   farmakoterapie   patofyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lineární modely MeSH
• mladiství MeSH
• mladý dospělý MeSH
• multivariační analýza MeSH
• narkolepsie komplikace   farmakoterapie   patofyziologie   MeSH
• průřezové studie MeSH
• senioři MeSH
• spotřeba kyslíku * fyziologie   MeSH
• stupeň závažnosti nemoci MeSH
• věkové faktory MeSH
• zátěžový test MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Histaminergic neurons are crucial to maintain wakefulness, but their role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients with narcolepsy. METHODS: For this randomised, double-blind, placebo-controlled trial we recruited patients with narcolepsy from 16 sleep centres in nine countries (Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, and Ukraine). Patients were eligible if they were aged 18 years or older, diagnosed with narcolepsy with cataplexy according to version two of the International Classification of Sleep Disorders criteria, experienced at least three cataplexies per week, and had excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via an interactive web response system to randomly assign patients to receive either pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks of four. Participants and investigators were masked to treatment allocation. Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 mg). The primary endpoint was the change in the average number of cataplexy attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) between the 2 weeks of baseline and the 4 weeks of stable dosing period. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01800045. FINDINGS: The trial was done between April 19, 2013, and Jan 28, 2015. We screened 117 patients, 106 of whom were randomly assigned to treatment (54 to pitolisant and 52 to placebo) and, after dropout, 54 patients from the pitolisant group and 51 from the placebo group were included in the intention-to-treat analysis. The WCR during the stable dosing period compared with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; WCRfinal/baseline=0·25) in patients who received pitolisant and 38% (WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p<0·0001). Treatment-related adverse events were significantly more common in the pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51; p=0·048). There were no serious adverse events, but one case of severe nausea in the pitolisant group. The most frequent adverse events in the pitolisant group (headache, irritability, anxiety, and nausea) were mild or moderate except one case of severe nausea. No withdrawal syndrome was detected following pitolisant treatment; one case was detected in the placebo group. INTERPRETATION: Pitolisant was well tolerated and efficacious in reducing cataplexy. If confirmed in long-term studies, pitolisant might constitute a useful first-line therapy for cataplexy in patients with narcolepsy, for whom there are currently few therapeutic options. FUNDING: Bioprojet, France.

• MeSH
• antagonisté histaminového receptoru H3 terapeutické užití   MeSH
• databáze bibliografické statistika a číselné údaje   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• kataplexie farmakoterapie   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• narkolepsie komplikace   MeSH
• následné studie MeSH
• piperidiny terapeutické užití   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antagonisté histaminového receptoru H3 MeSH
• piperidiny MeSH
• pitolisant MeSH Prohlížeč

Narcolepsy-cataplexy (NC) is a chronic neurological disease with suggested autoimmune etiopathogenesis. Nicotine stimulates central nervous system and smoking increases the risk of autoimmune diseases. Assessment of smoking habits and its correlation to clinical parameters among 87 adult NC patients (38 male, 49 female) included night polysomnography and multiple sleep latency test. In our sample, 43.7% NC patients were regular smokers, and 19.5% former smokers compared to 22.2%, and 12.6%, respectively, in the general population. Patients started to smoke in the mean age of 20.0 (SD ±6.0) years. 72.2% of NC smokers started to smoke before the onset of NC and the mean of the delay between smoking onset and NC onset was 9.1 (±5.8) years. We found a direct correlation between smoking duration and the number of awakenings, duration of N1 sleep, REM sleep latency, and apnoea/hypopnoea index (AHI), and, on the contrary, indirect correlation between smoking duration and N3 sleep duration, showing that smoking duration consistently correlates with sleep macrostructure. Smoking is highly prevalent in NC and has relationship with clinical features of NC.

• Klíčová slova
• Etiopathogenesis, Narcolepsy-cataplexy, Nicotine, Smoking, Stimulating effect,
• MeSH
• dospělí MeSH
• kataplexie diagnóza   farmakoterapie   epidemiologie   MeSH
• komorbidita MeSH
• kouření epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• narkolepsie diagnóza   farmakoterapie   epidemiologie   MeSH
• polysomnografie MeSH
• prevalence MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stimulanty centrálního nervového systému terapeutické užití   MeSH
• syndromy spánkové apnoe epidemiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• stimulanty centrálního nervového systému MeSH

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease-specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web-based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post-marketing medication side-effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials.

• Klíčová slova
• European Narcolepsy Centres, epidemiology, multicentre studies, narcolepsy, prospective data collection, standardized prospective database,
• MeSH
• databáze faktografické * normy   MeSH
• dospělí MeSH
• fenotyp MeSH
• internet MeSH
• kataplexie farmakoterapie   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• narkolepsie * farmakoterapie   epidemiologie   MeSH
• postmarketingový dozor MeSH
• prospektivní studie MeSH
• registrace * normy   MeSH
• řízení kvality MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• šíření informací MeSH
• vzácné nemoci farmakoterapie   epidemiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH

BACKGROUND: Narcolepsy with cataplexy is a debilitating sleep disease of which some symptoms can be treated with antidepressants. The antidepressant escitalopram is considered the most specific serotonin reuptake inhibitor. PATIENTS AND METHODS: Ten patients (5 men and 5 women, age range 18-77 years) suffering from narcolepsy with cataplexy occurring at least weekly were treated with escitalopram 5 or 10 mg a day for 28-98 days. These patients were barred from taking any drugs influencing cataplexy and also had no other diseases affecting sleep or vigilance. RESULTS: The mean number of cataplexies per week in 8 compliant patients declined significantly from 6.7 (+/-SD=7.2) to 0.3 (+/-0.6), P=0.02 (Sign test). Cataplexy completely disappeared in 6 patients. Subjective daytime sleepiness, power of concentration, quality of night sleep and mood remained unchanged. During the treatment, two patients had ejaculation disturbances. Two patients withdrew from the therapy (one because of ejaculation disturbance, the other for unknown reason). CONCLUSION: Escitalopram proved to have anticataplectic effects in this small-scale open-label study.

• MeSH
• citalopram terapeutické užití   MeSH
• dospělí MeSH
• ejakulace účinky léků   fyziologie   MeSH
• kataplexie komplikace   farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• narkolepsie komplikace   farmakoterapie   MeSH
• retrospektivní studie MeSH
• selektivní inhibitory zpětného vychytávání serotoninu terapeutické užití   MeSH
• senioři MeSH
• spánek MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• citalopram MeSH
• selektivní inhibitory zpětného vychytávání serotoninu MeSH

A mutation in the HCRT locus was proved in 18-yrs old male suffering from narcolepsy-cataplexy. He has demonstrated cataplectic attacks (brief spells of head dropping provoked by laughter) as well as imperative sleep in spells of several minutes up to one hour since the age of six months. He has suffered from severe bulimia since five years; later hypnagogic hallucinations, sleep paralysis and unquiet nocturnal sleep accompanied by periodic limb movements appeared. Symptoms are partially controlled with methylphenidate and either imipramine, clomipramine or fluoxetine. Periodic leg movements poorly responded to L-DOPA and clonazepam treatment. He is HLA-DQB1*0602 negative. Repeated MSLT (over 16 years followed-up period) showed extremely short latency with predominant SOREMPs and also nocturnal PSG recordings revealed fragmented sleep with SOREMPs. This case report demonstrates that hypocretin (orexin) mutations in human can produce the full narcolepsy phenotype and validates data recently reported in dog and mouse models suggesting a role for hypocretin (orexin) in the pathophysiology of narcolepsy and the regulation of REM sleep.

• MeSH
• intracelulární signální peptidy a proteiny * MeSH
• kataplexie farmakoterapie   metabolismus   MeSH
• lidé MeSH
• mladiství MeSH
• narkolepsie farmakoterapie   metabolismus   MeSH
• neuropeptidy mozkomíšní mok   nedostatek   MeSH
• neurotransmiterové látky mozkomíšní mok   nedostatek   MeSH
• orexiny MeSH
• transportní proteiny mozkomíšní mok   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• intracelulární signální peptidy a proteiny * MeSH
• neuropeptidy MeSH
• neurotransmiterové látky MeSH
• orexiny MeSH
• transportní proteiny MeSH

• MeSH
• antidepresiva aplikace a dávkování   terapeutické užití   MeSH
• chinazoliny aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• imipramin farmakologie   MeSH
• kataplexie farmakoterapie   MeSH
• lidé MeSH
• narkolepsie farmakoterapie   MeSH
• spánek REM účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antidepresiva MeSH
• chinazoliny MeSH
• imipramin MeSH

• MeSH
• amfetamin terapeutické užití   MeSH
• elektroencefalografie MeSH
• fenmetrazin terapeutické užití   MeSH
• imipramin terapeutické užití   MeSH
• kataplexie farmakoterapie   MeSH
• lidé MeSH
• narkolepsie farmakoterapie   MeSH
• spánek REM účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amfetamin MeSH
• fenmetrazin MeSH
• imipramin MeSH