RESUMO
Narcolepsy type 1 (NT1) is associated with severe loss of orexin neurons and characterized by symptoms including excessive daytime sleepiness and cataplexy. Current medications indicated for NT1 often show limited efficacy, not addressing the full spectrum of symptoms, demonstrating a need for novel drugs. We discovered a parenteral orexin receptor 2 (OX2R) agonist, danavorexton, and an orally available OX2R agonist, TAK-994; both improving NT1 phenotypes in mouse models and individuals with NT1. However, danavorexton has limited oral availability and TAK-994 has a risk of off-target liver toxicity. To avoid off-target-based adverse events, a highly potent molecule with low effective dose is preferred. Here, we show that a novel OX2R-selective agonist, TAK-861 [N-{(2S,3R)-4,4-Difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide], activates OX2R with a half-maximal effective concentration of 2.5 nM and promotes wakefulness at 1 mg/kg in mice and monkeys, suggesting ~ tenfold higher potency and lower effective dosage than TAK-994. Similar to TAK-994, TAK-861 substantially ameliorates wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 and orexin-tTA;TetO DTA mice (NT1 mouse models). Compared with modafinil, TAK-861 induces highly correlated brain-wide neuronal activation in orexin-tTA;TetO DTA mice, suggesting efficient wake-promoting effects. Thus, TAK-861 has potential as an effective treatment for individuals with hypersomnia disorders including narcolepsy, potentially with a favorable safety profile.
Assuntos
Modelos Animais de Doenças , Narcolepsia , Receptores de Orexina , Vigília , Animais , Narcolepsia/tratamento farmacológico , Receptores de Orexina/agonistas , Receptores de Orexina/metabolismo , Vigília/efeitos dos fármacos , Camundongos , Administração Oral , Fenótipo , Masculino , HumanosRESUMO
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a published article in the journal Sleep. Narcolepsy is a sleep condition that has 2 different subtypes: narcolepsy type 1 and narcolepsy type 2. These are called NT1 and NT2 for short. Sodium oxybate (SXB) is approved to treat excessive daytime sleepiness (EDS) and cataplexy. People with NT1 and NT2 both have EDS, but cataplexy is only present in people with NT1. Limited information is available about how SXB works in people with NT2. This is because previous trials have included only people with NT1 or people with unspecified narcolepsy. For more than 20 years, the only available formulation of this medicine had to be given twice during the night. Many people with narcolepsy find that chronically waking up in the middle of the night for a second dose of SXB is disruptive to themselves or others in their household. People have also reported sleeping through alarm clocks, missing their second dose, and feeling worse the next day. Some people have accidentally taken the second dose too early, putting them at risk for serious adverse effects. These adverse effects may include slow breathing, low blood pressure, or sedation. The US Food and Drug Administration (FDA) approved a medicine called LUMRYZ™ (sodium oxybate) for extended-release oral suspension in May 2023. LUMRYZ is a once-nightly formulation of SXB (ON-SXB for short) and is taken as a single dose before bedtime. This medicine treats EDS and muscle weakness (also known as cataplexy) in people with narcolepsy. A clinical trial called REST-ON studied ON-SXB to find out if it was better at treating narcolepsy symptoms than a medicine with no active ingredients (placebo). This summary describes a study that tested whether ON-SXB was better than placebo at treating narcolepsy symptoms in people with NT1 or NT2. WHAT WERE THE RESULTS?: This study showed that compared to people who took placebo, people who took ON-SXB were able to stay awake longer during the day, felt less sleepy during the daytime, had less cataplexy, and had more improvements in their symptoms overall than people who took placebo. WHAT DO THE RESULTS MEAN?: ON-SXB has been proven effective for people with NT1 or NT2. Unlike prior formulations of SXB, ON-SXB is taken once at bedtime, without requiring waking up in the middle of the night for a second dose.
Assuntos
Narcolepsia , Oxibato de Sódio , Humanos , Oxibato de Sódio/uso terapêutico , Oxibato de Sódio/administração & dosagem , Narcolepsia/tratamento farmacológico , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológicoRESUMO
BACKGROUND: Treatment adherence (TA) in narcolepsy is a complex phenomenon influenced by various factors beyond patient-related aspects. The management of narcolepsy involves non-pharmacological and symptomatic pharmacological treatment. Factors such as chronic daytime sleepiness, cognitive deficits, psychiatric comorbidities and adverse effects of pharmacological treatment are aspects of narcolepsy that could undermine TA, impacting patients' ability or willingness to consistently follow treatment plans. The aim of this study was to identify the factors influencing TA in narcolepsy and to determine the most significant barriers to adherence. METHODS: An online survey was conducted during the pandemic, assessing demographic and clinical data, medication usage, and adverse effects of treatment. Various questionnaires, such as the Adherence Barriers Questionnaire (ABQ) and Epworth Sleepiness Scale (ESS), were utilized. The ABQ identified patient-specific barriers to medication adherence, while the Patient Health Questionnaire (PHQ-9) assessed depressive symptoms. RESULTS: We analyzed 243 narcolepsy patients (77 % female, mean age 35.7 ± 12.3 years) with 71 % having narcolepsy type 1 (NT1). The average ESS score was 16.4 (SD ± 3.7). Adherence barriers (AB) were identified in 89 % of patients (216/243) based on ABQ score. The most common barriers reported were "Forgetfulness" (77 %), "Depression" (57 %), and "Side effect-driven medication reduction/stopping behavior" (49 %). Approximately 72 % of patients reported side effects from their narcolepsy medication, leading to discontinuation in 78 % of cases. A moderate correlation was found between the severity of adherence barriers (ABQ score) and levels of depression (PHQ-9 score; rs = 0.412, p = 00.000), as well as ESS score (p = . 048). The results of this study may have been influenced by the pandemic situation. CONCLUSION: Adherence barriers are common (89 %) and diverse among people with narcolepsy. Many barriers are related to excessive daytime sleepiness (EDS), cognitive deficits or depressive symptoms, highlighting the importance of recognizing and addressing them for optimal TA. Medication side effects, especially occurring when polypharmacology is utilized, also significantly contribute to adherence challenges. Effective communication regarding therapy adherence and improved detection and management of EDS and depression are crucial for enhancing TA in narcolepsy patients.
Assuntos
Adesão à Medicação , Narcolepsia , Humanos , Narcolepsia/tratamento farmacológico , Narcolepsia/psicologia , Feminino , Masculino , Adulto , Inquéritos e Questionários , Adesão à Medicação/psicologia , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Depressão/tratamento farmacológicoAssuntos
Narcolepsia , Antagonistas dos Receptores de Orexina , Distúrbios do Início e da Manutenção do Sono , Humanos , Antagonistas dos Receptores de Orexina/uso terapêutico , Antagonistas dos Receptores de Orexina/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Narcolepsia/tratamento farmacológico , Metanálise como AssuntoRESUMO
ABSTRACT: Wolfram syndrome 1 (WS1) is a rare, autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, insulin-dependent diabetes mellitus, optic atrophy, and deafness resulting from loss-of-function genetic variants in the WFS1 gene. Individuals with WS1 manifest a spectrum of neuropsychiatric disorders. Here, we report a pediatric case of WS1, which stemmed from a novel biallelic WFS1 loss-of-function genetic variant. The individual initially presented with obsessive-compulsive disorder, which was successfully managed by fluvoxamine. After 2 months, the child manifested excessive daytime sleepiness. Clinical evaluation and sleep recordings revealed a diagnosis of narcolepsy type 2. Excessive daytime sleepiness was improved with methylphenidate. To the best of our knowledge, this is the first report of narcolepsy in WS1, which possibly arose during a progressive neurodegenerative process. We emphasize the need for in-depth screening for neuropsychiatric phenotypes and sleep-related disorders in WS1, for clinical management, which significantly improves the quality of life.
Assuntos
Narcolepsia , Transtorno Obsessivo-Compulsivo , Síndrome de Wolfram , Humanos , Feminino , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/genética , Síndrome de Wolfram/fisiopatologia , Síndrome de Wolfram/complicações , Narcolepsia/diagnóstico , Narcolepsia/fisiopatologia , Narcolepsia/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Criança , Proteínas de Membrana/genéticaRESUMO
The history of narcolepsy research began with the pioneering work of Jean-Baptiste-Édouard Gélineau in the late 19th century. In the 1880s, Gélineau introduced the term "narcolepsy" to describe a condition characterized by sudden and uncontrollable episodes of sleep. His clinical descriptions laid the foundation for our understanding of this complex disorder. Over the last half-century, the pharmacological landscape for narcolepsy treatment has evolved remarkably, shifting from merely managing symptoms to increasingly targeting its underlying pathophysiology. By the 1930s, treatments such as ephedrine and amphetamine were introduced to alleviate excessive daytime sleepiness, marking significant advancements in narcolepsy management. These stimulants provided temporary relief, helping patients maintain wakefulness during the day. As research progressed, the focus shifted towards understanding the disorder's underlying mechanisms. The discovery of orexin (also known as hypocretin) in the late 1990s revolutionized the field. This breakthrough underscored the importance of orexin in regulating sleep-wake cycles and provided new targets for pharmacological intervention. Looking ahead, the future of narcolepsy pharmacotherapy is poised for further innovation. The ongoing exploration of orexin receptor agonists and the potential development of neuroprotective therapeutic targets underscore a promising horizon. Emerging research into the genetic and immunological underpinnings of narcolepsy opens new avenues for personalized medicine approaches and the identification of biomarkers for more precise treatment strategies. Additionally, the refinement of existing treatments through improved delivery systems and the investigation of combination therapies offer opportunities for enhanced efficacy and improved quality of life for patients with narcolepsy.
Assuntos
Narcolepsia , Narcolepsia/tratamento farmacológico , Humanos , História do Século XX , História do Século XXI , Orexinas , Animais , Estimulantes do Sistema Nervoso Central/uso terapêuticoRESUMO
While typically thought of as an illicit substance, oxybate salts or gamma-hydroxybutyrate (GHB) has more recently been prescribed to treat narcolepsy by enhancing night-time sleep resulting in decreased daytime drowsiness. This case involves a college-aged female with prescribed GHB for narcolepsy who took her second nightly dose too early. This resulted in mental depression, respiratory failure, intubation and mechanical ventilation. The patient was successfully extubated in the intensive care unit several hours later with no residual morbidity. We were unable to identify any prior reports of mixed-salt oxybate toxicity following mistimed drug administration. This case should serve as a warning to emergency physicians to be on the lookout for GHB as part of the differential diagnosis for patients with narcolepsy presenting with altered mental status. It should also serve as a warning to patients and prescribers that this medication can have outcomes that require immediate medical intervention.
Assuntos
Overdose de Drogas , Narcolepsia , Respiração Artificial , Insuficiência Respiratória , Oxibato de Sódio , Humanos , Feminino , Narcolepsia/tratamento farmacológico , Narcolepsia/diagnóstico , Oxibato de Sódio/intoxicação , Oxibato de Sódio/efeitos adversos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/terapia , Magnésio , Potássio/sangue , Potássio/uso terapêutico , Erros de MedicaçãoRESUMO
INTRODUCTION: Narcolepsy is a chronic and rare neurological disorder characterized by disordered sleep. Based on animal models and further research in humans, the dysfunctional orexin system was identified as a contributing factor to the pathophysiology of narcolepsy. Animal models played a larger role in the discovery of some of the pharmacological agents with established benefit/risk profiles. AREAS COVERED: In this review, the authors examine the phenotypes observed in animal models of narcolepsy and the characteristics of clinically used pharmacological agents in these animal models. Additionally, the authors compare the effects of clinically used pharmacological agents on the phenotypes in animal models with those observed in narcolepsy patients. EXPERT OPINION: Research in canine and mouse models have linked narcolepsy to the O×R2mutation and orexin deficiency, leading to new diagnostic criteria and a drug development focus. Advancements in pharmacological therapies have significantly improved narcolepsy management, with insights from both clinical experience and from animal models having led to new treatments such as low sodium oxybate and solriamfetol. However, challenges persist in addressing symptoms beyond excessive daytime sleepiness and cataplexy, highlighting the need for further research, including the development of diurnal animal models to enhance understanding and treatment options for narcolepsy.
Assuntos
Modelos Animais de Doenças , Desenvolvimento de Medicamentos , Descoberta de Drogas , Narcolepsia , Orexinas , Narcolepsia/tratamento farmacológico , Narcolepsia/fisiopatologia , Animais , Humanos , Cães , Descoberta de Drogas/métodos , Camundongos , Orexinas/metabolismo , FenótipoRESUMO
OBJECTIVE: The executive function profile in patients with narcolepsy type 1 (NT1) has been mentioned; however, limited research exists on children and adolescent patients with NT1.This study aims to assess executive function in children and adolescent patients with NT1 in China, examine potential influencing factors and evaluate the short-term treatment effect on executive function. METHODS: 53 NT1 patients (36 males, age 12.2 ± 3.4 years) and 37 healthy controls (23 males, age 12.2 ± 2.5 years) underwent self-reported measures assessing subjective sleepiness, depression, anxiety and sleep quality. A comprehensive neuropsychological test was administered to assess executive function domains, including processing speed, inhibitory control, cognitive flexibility and working memory. These assessments were repeated in NT1 patients after three-day regular drug treatment. RESULTS: NT1 patients exhibited higher levels of excessive daytime sleepiness, depression, anxiety, and poor sleep quality compared to healthy controls. Patients showed impaired processing speed, inhibitory control and cognitive flexibility (p < 0.05), whereas working memory was unaffected (p > 0.05). Regression analysis revealed that parameters from sleep monitoring, such as sleep efficiency and sleep latency, were correlated with executive function performance after controlling for age, gender, and education years. The short-term treatment led to improvements in inhibitory control, cognitive flexibility, and working memory. CONCLUSION: The findings showed that executive function was impaired among children and adolescent patients with NT1, which was associated with objective sleep parameters. Furthermore, this study emphasizes the necessity of neuropsychological assessments and early interventions among children and adolescent NT1 patients.
Assuntos
Função Executiva , Narcolepsia , Testes Neuropsicológicos , Humanos , Masculino , Narcolepsia/tratamento farmacológico , Narcolepsia/psicologia , Narcolepsia/fisiopatologia , Feminino , Função Executiva/fisiologia , Adolescente , Criança , Testes Neuropsicológicos/estatística & dados numéricos , Memória de Curto Prazo/fisiologia , China , Depressão/psicologia , Ansiedade/psicologia , Qualidade do SonoRESUMO
STUDY OBJECTIVES: Low-sodium oxybate (LXB; calcium, magnesium, potassium, and sodium oxybates; Xywav) contains the same active moiety as high-sodium oxybates (SXBs; SXB [Xyrem] and fixed-dose SXB [Lumryz]), with 92% less sodium, and is approved in the United States for treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy, and idiopathic hypersomnia in adults. Patients with narcolepsy have increased cardiovascular risk relative to people without narcolepsy. LXB's lower sodium content is recognized by the United States Food and Drug Administration in the narcolepsy population as clinically meaningful in reducing cardiovascular morbidity compared with SXBs. The Substitution of Equal Grams of Uninterrupted Xyrem to Xywav study (NCT04794491) examined the transition experience of patients with narcolepsy switching from SXB to LXB. METHODS: Eligible participants were aged 18-80 years with narcolepsy type 1 or 2 on a stable SXB dose/regimen. After 2 weeks, participants transitioned gram-per-gram to LXB for 6 weeks, with opportunity for subsequent titration. Assessments included the Epworth Sleepiness Scale, Patient Global Impression of change, Ease of Switching Medication Scale, and Forced Preference Questionnaire. RESULTS: The study enrolled 62 participants at baseline; 60 transitioned to LXB and 54 completed the study. At baseline and end of the LXB intervention/early discontinuation, respectively, mean total doses were 8.0 and 8.0 g/night; mean Epworth Sleepiness Scale scores were 9.4 and 8.8. Most participants reported improvement (45%) or no change (48%) in narcolepsy symptoms on the Patient Global Impression of change, reported the transition to LXB was "easy" (easy, extremely easy, not difficult at all; 93%) on the Ease of Switching Medication Scale, and preferred LXB compared with SXB (79%) on the Forced Preference Questionnaire, most commonly due to the lower sodium content. CONCLUSIONS: Most participants switched from SXB to LXB with minimal modifications of dose/regimen and reported the transition process was easy. Effectiveness of oxybate treatment was maintained on LXB, and most participants preferred LXB to SXB. No new safety or tolerability issues were identified. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: An Interventional Safety Switch Study (Segue Study) of XYWAV in Narcolepsy; URL: https://classic.clinicaltrials.gov/ct2/show/NCT04794491; Identifier: NCT04794491. CITATION: Macfadden W, Leary EB, Fuller DS, Kirby MT, Roy A. Effectiveness and optimization of low-sodium oxybate in participants with narcolepsy switching from a high-sodium oxybate: data from the Substitution of Equal Grams of Uninterrupted Xyrem to Xywav study. J Clin Sleep Med. 2024;20(9):1467-1477.
Assuntos
Narcolepsia , Oxibato de Sódio , Humanos , Narcolepsia/tratamento farmacológico , Oxibato de Sódio/uso terapêutico , Oxibato de Sódio/administração & dosagem , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Resultado do Tratamento , Adolescente , Substituição de Medicamentos/métodos , Adulto Jovem , Idoso , Relação Dose-Resposta a DrogaRESUMO
BACKGROUND: Patients with narcolepsy often experience disturbed nighttime sleep. Modafinil is commonly prescribed for hypersomnolence, but its impacts on nocturnal sleep remain unclear. This study uses actigraphy to examine the effect of modafinil on both hypersomnolence and nocturnal sleep patterns in patients with narcolepsy. METHODS: Prior to treatment, 87 patients with narcolepsy wore an actigraphy for 7-14 days to assess their nighttime sleep. After evaluation, they received a daily dose of 200-400 mg of modafinil in the morning and wore an actigraphy again six months after initiating treatment. Questionnaires, including the Epworth-Sleepiness-Scale (ESS), the Visual-Analogue-for-Hypersomnolence (VAS), and the Short-Form-36-Health-Survey (SF-36), were used to evaluate hypersomnolence and quality of life both before and after treatment. Paired t-tests and independent samples t-tests were used for pre- and post-treatment comparisons and subgroup analysis. We used the Pearson's correlation test to measure the correlations between the sleep parameters of the actigraphy and data of the questionnaires. RESULTS: Improvements in hypersomnolence were noted following modafinil treatment, and we observed no significant deterioration in nocturnal sleep parameters by the actigraphy. The total number of awakenings by actigraphy significantly decreased (p = 0.005), especially in females (p = 0.008), while sleep onset latency significantly increased in children/adolescents (p = 0.014). Correlations were found between the sleep parameters of the actigraphy and ESS, VAS, and SF-36 scores. CONCLUSION: Modafinil treatment may not worsen nighttime sleep in patients with narcolepsy. However, it should be administered with care in children and adolescents.
Assuntos
Actigrafia , Compostos Benzidrílicos , Modafinila , Narcolepsia , Qualidade de Vida , Promotores da Vigília , Humanos , Modafinila/uso terapêutico , Modafinila/farmacologia , Narcolepsia/tratamento farmacológico , Feminino , Masculino , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/farmacologia , Adulto , Promotores da Vigília/uso terapêutico , Promotores da Vigília/farmacologia , Adolescente , Estudos de Coortes , Inquéritos e Questionários , Pessoa de Meia-Idade , Adulto Jovem , Sono/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/uso terapêutico , Estimulantes do Sistema Nervoso Central/farmacologia , Criança , Resultado do TratamentoRESUMO
Narcolepsy is a primary disorder of the central nervous system resulting from genetic, environmental, and immunological interactions defined as excessive daytime sleepiness plus cataplexy, hallucinations, sleep paralysis, and sleep fragmentation. The pathophysiology is not entirely known, but the interaction among genetic predisposition, environmental exposition, and immune component with consequent hypocretin-1 deficiency is the model to explain narcolepsy type I. The mechanism of narcolepsy type II is less understood. There is a delay of over ten years for the diagnosis of narcolepsy around the world. Patients with narcolepsy have many comorbidities with a negative impact on quality of life. The treatment of narcolepsy must contain an educational approach for the family, coworkers, and patients. Scheduled naps and sleep hygiene are essential to minimize the dose of medications. Much progress has been seen in the pharmacological treatment of narcolepsy with new stimulants, different presentations of oxybate, and recent studies with orexin agonists. Narcolepsy is a rare disease that needs to be more understood and highlighted to avoid delayed diagnosis and severe disabilities in patients.
A narcolepsia é um distúrbio primário do sistema nervoso central resultante das interações genéticas, ambientais e imunológicas definidas como sonolência diurna excessiva mais cataplexia, alucinações, paralisia do sono e fragmentação do sono. A fisiopatologia não é completamente conhecida, mas a interação entre predisposição genética, exposição ambiental e componente imunológico com consequente deficiência de hipocretina-1 é o modelo para explicar a narcolepsia tipo I. O mecanismo da narcolepsia tipo II é menos compreendido. Há um atraso de mais de dez anos para o diagnóstico da narcolepsia em todo o mundo. Pacientes com narcolepsia apresentam muitas comorbidades com impacto negativo na qualidade de vida. O tratamento da narcolepsia deve conter uma abordagem educativa para a família, colegas de trabalho e pacientes. Cochilos programados e higiene do sono são importantes para minimizar a dose dos medicamentos. Muito progresso foi observado no tratamento farmacológico da narcolepsia com novos estimulantes, diferentes apresentações de oxibato e estudos recentes com agonistas de orexina. A narcolepsia é uma doença rara que precisa ser mais compreendida e destacada para evitar atrasos no diagnóstico e incapacidades graves nos pacientes.
Assuntos
Cataplexia , Narcolepsia , Neurologia , Humanos , Qualidade de Vida , Narcolepsia/tratamento farmacológico , Narcolepsia/genética , Narcolepsia/diagnóstico , Cataplexia/tratamento farmacológico , Cataplexia/genética , Cataplexia/diagnóstico , SonoRESUMO
STUDY OBJECTIVES: Narcolepsy type 2 (NT2) is an understudied central disorder of hypersomnolence sharing some similarities with narcolepsy type 1 and idiopathic hypersomnia (IH). We aimed: (1) to assess systematically the symptoms in patients with NT2, with self-reported questionnaires: Epworth Sleepiness Scale (ESS), Narcolepsy Severity Scale (NSS), IH Severity Scale (IHSS), and (2) to evaluate the responsiveness of these scales to treatment. METHODS: One hundred and nine patients with NT2 (31.4â ±â 12.2 years old, 47 untreated) diagnosed according to ICSD-3 were selected in a Reference Center for Narcolepsy. They all completed the ESS, subgroups completed the modified NSS (NSS-2, without cataplexy items) (nâ =â 95) and IHSS (nâ =â 76). Some patients completed the scales twice (before/during treatment): 42 ESS, 26 NSS-2, and 30 IHSS. RESULTS: Based on NSS-2, all untreated patients had sleepiness, 58% disrupted nocturnal sleep, 40% hallucinations, and 28% sleep paralysis. On IHSS, 76% reported a prolonged nocturnal sleep, and 83% sleep inertia. In the independent sample, ESS and NSS-2 scores were lower in treated patients, with same trend for IHSS scores. After treatment, ESS, NSS-2, and IHSS total scores were lower, with a mean difference of 3.7â ±â 4.1, 5.3â ±â 6.7, and 4.1â ±â 6.2, respectively. The minimum clinically important difference between untreated and treated patients were 2.1 for ESS, 3.3 for NSS-2, and 3.1 for IHSS. After treatment, 61.9% of patients decreased their ESSâ >â 2 points, 61.5% their NSS-2â >â 3 points, and 53.3% their IHSSâ >â 3 points. CONCLUSIONS: NSS-2 and IHSS correctly quantified symptoms' severity and consequences in NT2, with good performances to objectify response to medications. These tools are useful for monitoring and optimizing NT2 management, and for use in clinical trials.
Assuntos
Hipersonia Idiopática , Narcolepsia , Índice de Gravidade de Doença , Humanos , Narcolepsia/diagnóstico , Narcolepsia/fisiopatologia , Narcolepsia/tratamento farmacológico , Masculino , Feminino , Adulto , Hipersonia Idiopática/diagnóstico , Hipersonia Idiopática/fisiopatologia , Inquéritos e Questionários , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/fisiopatologia , Alucinações/diagnóstico , Alucinações/fisiopatologia , Pessoa de Meia-Idade , Modafinila/uso terapêutico , Adulto Jovem , Paralisia do Sono/diagnóstico , Paralisia do Sono/fisiopatologia , Autorrelato , Promotores da Vigília/uso terapêuticoRESUMO
Pitolisant, a novel histamine H3-receptor antagonist, holds significant promise for treating narcolepsy. However, a petition, which highlighted that pitolisant was associated with deaths during clinical trials, has propelled it into the spotlight of widespread societal attention on April 3, 2023. Till now, the clinical safety of pitolisant remains a heatedly debated topic. This study aimed to offer a comprehensive assessment of the safety profile of pitolisant in real-world clinical settings. Adverse event reports where pitolisant was the primary suspect drug were extracted from the FDA Adverse Event Reporting System database. The clinical characteristics and concomitant drugs of the pitolisant-associated adverse events were analyzed. The potential adverse event signals of pitolisant were explored using four disproportionality analysis methods. Furthermore, the difference in pitolisant-associated adverse event signals was investigated concerning sex, age, weight, and dose. A total of 526 reports and 1695 adverse events with pitolisant as the primary suspected drug were identified. The most significant adverse event signals were generally mild and of short duration. The concomitant drugs of pitolisant were highly intricate, mainly included drugs for treating narcolepsy as well as antidepressants. Seven new significant adverse event signals emerged. The safety profile of pitolisant exhibited no significant differences across age and dose groups, although slight variations were observed in relation to sex and weight. The findings from reports of death and life-threatening outcomes underscore the importance of enhanced monitoring for cardiac and respiratory adverse reactions when utilizing pitolisant. This study provided a broader understanding of the safety profile of pitolisant.
Assuntos
Narcolepsia , Farmacovigilância , Humanos , Estudos Retrospectivos , Narcolepsia/tratamento farmacológico , Piperidinas/efeitos adversosRESUMO
Many components of sleep are disrupted in patients with narcolepsy, including sleep quality, sleep architecture, and sleep stability (ie, frequent awakenings/arousals and frequent shifts from deeper to lighter stages of sleep). Sodium oxybate, dosed twice nightly, has historically been used to improve sleep, and subsequent daytime symptoms, in patients with narcolepsy. Recently, new formulations have been developed to address the high sodium content and twice-nightly dosing regimen of sodium oxybate: low-sodium oxybate and once-nightly sodium oxybate. To date, no head-to-head trials have been conducted to compare the effects of each oxybate product. This review aims to give an overview of the existing scientific literature regarding the impact of oxybate dose and regimen on sleep architecture and disrupted nighttime sleep in patients with narcolepsy. Evidence from 5 key clinical trials, as well as supporting evidence from additional studies, suggests that sodium oxybate, dosed once- and twice-nightly, is effective in improving sleep, measures of sleep architecture, and disrupted nighttime sleep in patients with narcolepsy. Direct comparison of available efficacy and safety data between oxybate products is complicated by differences in trial designs, outcomes assessed, and statistical analyses; future head-to-head trials are needed to better understand the advantage and disadvantages of each agent.
Assuntos
Narcolepsia , Oxibato de Sódio , Humanos , Oxibato de Sódio/efeitos adversos , Polissonografia , Sono , Narcolepsia/tratamento farmacológico , Narcolepsia/complicações , Qualidade do SonoRESUMO
PURPOSE: - Narcolepsy type 1 (NT1) is a rare chronic sleep disorder, usually arising by adolescence that negatively impacts quality of life. It is characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis and sleep fragmentation. The goals of this work were to characterize NT1 adolescents regarding sleep characteristics, health-related quality of life (HRQoL) and future life perspectives and later to compare this group with a control group of healthy adolescents (HA). METHODS: - Transversal descriptive/analytical study including NT1 patients followed in a sleep center of a tertiary hospital and 23 HA. Data were collected through an online survey, fulfilled by the participants, including four sections: demographics; questionnaire evaluating sleep and EDS; questionnaire evaluating HRQoL; inquiry regarding future perspectives. An extra section for the NT1 group only, comprising questions about the characterization of narcolepsy, was included. RESULTS: 22 NT1 adolescents were included, with a median age of 15.0 years-old. Beyond EDS, all had presented cataplexy - 19 still reported it. Twenty patients took psychostimulants regularly for EDS, while 13 patients took venlafaxine or fluoxetine for cataplexy. Nineteen adolescents took regular naps and 19 maintained psychological appointments. Self-reported sleep quality was similar between groups (p = 0.112). EDS was identified in seven NT1 patients and none in the control group. HRQOL was significantly lower in NT1 patients only for the physical well-being domain (p = 0.001). Regarding future perspectives, results were similar, except for a lower probability of getting a driver's license in NT1 patients, despite no statistical significance (p = 0.104). DISCUSSION: Daytime sleepiness is difficult to control in NT1, despite specialized treatment. HRQoL was similar between groups in all domains except for the physical well-being. Despite good adherence to pharmacological and non-pharmacological treatments (namely psychological therapy) that account for these good results, the physical well-being domain is difficult to manage.
Assuntos
Cataplexia , Distúrbios do Sono por Sonolência Excessiva , Narcolepsia , Humanos , Adolescente , Cataplexia/tratamento farmacológico , Qualidade de Vida , Centros de Atenção Terciária , Narcolepsia/tratamento farmacológicoRESUMO
STUDY OBJECTIVES: Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs. METHODS: Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms. RESULTS: Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group. CONCLUSION: This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.
Assuntos
Narcolepsia , Distúrbios do Início e da Manutenção do Sono , Paralisia do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Antagonistas dos Receptores de Orexina/efeitos adversos , Narcolepsia/tratamento farmacológicoRESUMO
STUDY OBJECTIVES: We examined body mass index (BMI) changes associated with sodium oxybate treatment (SXB) in pediatric patients with narcolepsy with cataplexy who participated in a double-blind, placebo-controlled, randomized withdrawal study and an open-label continuation period. METHODS: Participants were aged 7-16 years at screening. SXB-naive participants titrated to twice-nightly dosing of SXB then entered a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period. After a 2-week randomized withdrawal period, all participants entered an open-label safety period (OLP; main study duration: ≤ 52 weeks). Participants who completed the OLP were allowed to enter the open-label continuation period (an additional 1-2 years). BMI percentile categories were defined as underweight (< 5th), normal (5th to < 85th), overweight (≥ 85th to < 95th), and obese (≥ 95th). RESULTS: Median BMI percentile decreased from baseline to OLP week 52 in SXB-naive participants who were normal weight at baseline (decreased from 77.0 to 35.0) or overweight/obese at baseline (98.0 to 86.7). Median BMI percentile decreased to a lesser extent in participants taking twice-nightly SXB at study entry who were normal weight at baseline (54.6 to 53.0) or overweight/obese at baseline (96.5 to 88.9). Shifts in BMI category from baseline to week 52 were sometimes noted. In SXB-naive participants, 9/10 (90.0%) who were overweight became normal weight, 7/25 (28.0%) who were obese became normal weight, 3/25 (12.0%) who were obese became overweight, and 1/16 (6.3%) who was normal weight became obese. In participants taking SXB at baseline, 5/8 (62.5%) who were overweight became normal weight, 3/6 (50.0%) who were obese became overweight, 1/14 (7.1%) who was normal weight became overweight, and 2/14 (14.3%) who were normal weight became underweight. Median BMI percentiles at months 6 and 12 of the open-label continuation period were similar to those at OLP end (OLP week 52). In SXB-naive participants, the evident BMI z-score decrease over time was relative to the screening values. CONCLUSIONS: Decreases in BMI percentile and z-score, and downward shifts in BMI category, were observed within 1 year of SXB treatment in pediatric participants with narcolepsy with cataplexy. BMI decreases plateaued after approximately 1 year. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of Xyrem With an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy; URL: https://clinicaltrials.gov/study/NCT02221869; Identifier: NCT02221869. CITATION: Dauvilliers Y, Lammers GJ, Lecendreux M, et al. Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy. J Clin Sleep Med. 2024;20(3):445-454.
Assuntos
Cataplexia , Narcolepsia , Oxibato de Sódio , Criança , Humanos , Índice de Massa Corporal , Narcolepsia/tratamento farmacológico , Obesidade/complicações , Sobrepeso/complicações , Oxibato de Sódio/uso terapêutico , Magreza , AdolescenteRESUMO
Daytime sleepiness is common amongst children and adolescents. Inadequate sleep duration, inappropriate school start times, and the delay in sleep phase of adolescence may all contribute. Nocturnal sleep disruption due to sleep disorders such as obstructive sleep apnea or restless legs syndrome/periodic limb movement disorder may also lead to daytime sleepiness. Profound sleepiness however, when occurring in the setting of adequate sleep duration, is rare amongst children and adolescents and may prompt consideration of a central disorder of hypersomnolence (CDH). Narcolepsy is the archetypal and most studied form of CDH and a detailed review of the presentation, evaluation, treatment of narcolepsy is included separately in this edition of Seminars in Pediatric Neurology. In addition to narcolepsy, 2 other forms of primary CDH exist, idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS). Onset of IH and KLS occurs most frequently during the pediatric age range and presentation may include signs of encephalopathy in addition to hypersomnolence. As such, they are of particular relevance to pediatric neurology and associated fields. Unfortunately, when compared to narcolepsy little is known about IH and KLS, at both the physiologic and clinical level. This review will focus on the presentation, evaluation, and management of idiopathic hypersomnia and Kleine-Levin syndrome in the pediatric population.
Assuntos
Encefalopatias , Distúrbios do Sono por Sonolência Excessiva , Hipersonia Idiopática , Síndrome de Kleine-Levin , Narcolepsia , Adolescente , Criança , Humanos , Síndrome de Kleine-Levin/terapia , Síndrome de Kleine-Levin/tratamento farmacológico , Hipersonia Idiopática/diagnóstico , Hipersonia Idiopática/terapia , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/etiologia , Distúrbios do Sono por Sonolência Excessiva/terapia , Narcolepsia/terapia , Narcolepsia/tratamento farmacológicoRESUMO
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a published article in the journal CNS Drugs. Narcolepsy is a rare sleep condition. Most people with narcolepsy experience disrupted nighttime sleep and have poor quality of sleep. Sometimes these symptoms are not easily diagnosed as a symptom of narcolepsy. Sodium oxybate is an approved treatment for narcolepsy. The only version of sodium oxybate that was available until 2023 required people to take their sodium oxybate at bedtime and then again in the middle of the night. The US Food and Drug Administration (FDA for short) has approved a once-nightly bedtime dose of sodium oxybate (ON-SXB for short, also known as FT218 or LUMRYZ™) to treat symptoms of narcolepsy in adults. These symptoms are daytime sleepiness and cataplexy, which is an episode of sudden muscle weakness. The once-nightly bedtime dose of ON-SXB removes the need for a middle-of-the-night dose of sodium oxybate. The REST-ON clinical study compared ON-SXB to a placebo (a substance that contains no medicine) to determine if it was better at treating symptoms of disrupted nighttime sleep associated with narcolepsy. This summary looks at whether; ON-SXB was better than placebo at treating symptoms of disrupted nighttime sleep. WHAT WERE THE RESULTS?: Compared to people who took placebo, people who took ON-SXB had fewer number of changes from deeper to lighter sleep stages and woke up less during the night. They also reported that they slept better at night and felt more refreshed when waking up in the morning. People with narcolepsy sometimes take alerting agents to help with sleepiness during the day, but alerting agents can cause difficulty sleeping at night. This study showed that people who took ON-SXB had better nighttime sleep even if they were taking alerting agents during the day. The most common side effects of ON-SXB included dizziness, nausea (feeling sick to your stomach), vomiting, headache, and bedwetting. WHAT DO THE RESULTS MEAN?: A once-nightly bedtime dose of ON-SXB is a narcolepsy treatment option for people without the need for a middle-of-the-night dose of sodium oxybate.