RESUMEN
Among mammals, there is a positive correlation between serum uric acid (UA) levels and life span. Humans have high levels of UA because they lack a functional urate oxidase (UOX) enzyme that is present in shorter lived mammals. Here, we show that male and female mice with UOX haploinsufficiency exhibit an age-related elevation of UA levels, and that the life span of female but not male UOX+/- mice is significantly increased compared to wild-type mice. Serum UA levels are elevated in response to treadmill exercise in UOX+/- mice, but not wild-type mice, and the endurance of the UOX+/- mice is significantly greater than wild-type mice. UOX+/- mice exhibit elevated levels of brain-derived neurotrophic factor, reduced brain damage and improved functional outcome in a model of focal ischemic stroke. Levels of oxidative protein nitration and lipid peroxidation are reduced in muscle and brain tissues of UOX+/- mice under conditions of metabolic and oxidative stress (running in the case of muscle and ischemia in the case of the brain), consistent with prior evidence that UA can scavenge peroxynitrite and hydroxyl radical. Our findings reveal roles for UA in life span determination, endurance and adaptive responses to brain injury, and suggest novel approaches for protecting cells against injury and for optimizing physical performance.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Accidente Cerebrovascular/tratamiento farmacológico , Ácido Úrico/farmacología , Animales , Humanos , Longevidad , Ratones Transgénicos , Estrés Oxidativo/efectos de los fármacosRESUMEN
Study Objectives: Insomnia is one of the most common disorders in the general population. Hypnotic medications are efficacious, but their use is limited by adverse events (AEs). This study evaluated the safety and efficacy of a novel forehead temperature-regulating device that delivers frontal cerebral thermal therapy (maintained at 14-16°C, equivalent to 57-61°F) for the treatment of insomnia. Methods: This was a prospective, randomized controlled trial involving two nights of therapy in 106 adults diagnosed with insomnia. The main outcome measures included latency to persistent sleep and sleep efficiency derived from polysomnographic (PSG) recordings and frequency and severity of AEs. Results: The safety profile was comparable to sham treatment. Statistically significant differences were not found in the two a priori co-primary endpoint measures absolute latency to persistent sleep (p = 0.092) or absolute sleep efficiency. Frontal cerebral thermal therapy produced improvements over sham in other convergent measures of sleep latency including relative changes from baseline in latency to persistent sleep (p = 0.013), the latency to stage 1 NREM sleep (p = 0.006), the latency to stage 2 NREM sleep (p = 0.002), a trend for the latency to stage 3 NREM sleep (p = 0.055), and an increase in the minutes of sleep during the first hour of the night (p = 0.024). Conclusions: Two-night frontal cerebral thermal therapy produced improvements in PSG measures of insomnia patients' ability to fall asleep and had a benign safety profile. Further studies are warranted to determine the role of this therapy in the longer-term management of insomnia. Trial Registration: clinicaltrials.gov Identifier: NCT01966211.
Asunto(s)
Frente/fisiología , Calefacción/métodos , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Sueño/fisiología , Adulto , Regulación de la Temperatura Corporal , Femenino , Humanos , Hipnóticos y Sedantes , Masculino , Persona de Mediana Edad , Polisomnografía , Estudios Prospectivos , Latencia del Sueño , Temperatura , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the effects of JZP-110 on the Maintenance of Wakefulness Test (MWT) with data censored to include only the first 20 min of a 40-min MWT. METHODS: In a 4-week, placebo-controlled crossover design (Study 201; N = 33) and a 12-week parallel-group design (Study 202; N = 93), JZP-110 was evaluated in narcolepsy patients using changes from baseline in the 40-min MWT as the primary endpoint. Effect sizes based on the change from baseline in mean MWT sleep latency were calculated using 20-min censored MWT data and compared to 40-min MWT data. RESULTS: In Study 201, mean (standard deviation) changes in MWT sleep latency were 12.7 (10.6) min with JZP-110 versus 0.9 (6.0) min with placebo (P = 0.0002) for 40-min data, and 8.9 (6.3) versus 0.4 (4.6) min for 20-min censored data (P < 0.0001). In Study 202, mean changes in MWT sleep latency were 12.8 (10.3) min with JZP-110 versus 2.1 (7.9) min with placebo (P < 0.0001) for 40-min data, and 8.9 (5.5) versus 1.1 (5.6) min for 20-min censored data (P < 0.0001). In Studies 201 and 202, respectively, Cohen's d effect sizes were large and numerically greater for 20-min censored data (1.54 and 1.41) versus 40-min data (1.37 and 1.17). CONCLUSIONS: In patients with narcolepsy, JZP-110 significantly improved the ability to stay awake compared with placebo, with large effect sizes using both the 40-min and 20-min censored MWT data.
Asunto(s)
Carbamatos/uso terapéutico , Narcolepsia/tratamiento farmacológico , Fenilalanina/análogos & derivados , Promotores de la Vigilia/uso terapéutico , Adulto , Carbamatos/efectos adversos , Estudios Cruzados , Femenino , Humanos , Masculino , Narcolepsia/diagnóstico , Fenilalanina/efectos adversos , Fenilalanina/uso terapéutico , Sueño/efectos de los fármacos , Factores de Tiempo , Resultado del Tratamiento , Vigilia/efectos de los fármacos , Promotores de la Vigilia/efectos adversosRESUMEN
STUDY OBJECTIVES: To evaluate the efficacy and safety of oral JZP-110, a second-generation wake-promoting agent with dopaminergic and noradrenergic activity, for treatment of impaired wakefulness and excessive sleepiness in adults with narcolepsy. METHODS: This was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial conducted at 28 centers in the United States. Patients were adults with narcolepsy who had baseline scores ≥ 10 on the Epworth Sleepiness Scale (ESS) and baseline sleep latency ≤ 10 min on the Maintenance of Wakefulness Test (MWT). Patients received a daily placebo (n = 49) or JZP-110 (n = 44) 150 mg/day weeks 1-4 and 300 mg/day weeks 5-12. Primary efficacy endpoints were change from baseline in average MWT sleep latency, and the Clinical Global Impression-Change (CGI-C); secondary endpoints were change from baseline in ESS score and Patient Global Impression-Change. RESULTS: Improvements were significantly greater with JZP-110 versus placebo on mean MWT sleep latency (4 w, 9.5 versus 1.4 min, P < 0.0001; 12 w, 12.8 versus 2.1 min, P < 0.0001), percentage of patients with CGI-C improvement (4 w, 80% versus 51%, P = 0.0066; 12 w, 86% versus 38%, P < 0.0001), and mean change in ESS (4 w, -5.6 versus -2.4, P = 0.0038; 12 w, -8.5 versus -2.5, P < 0.0001). Three JZP-110-treated patients (6.8%) discontinued due to adverse events (AEs). The most common AEs with JZP-110 versus placebo were insomnia (23% versus 8%), headache (16% versus 10%), nausea (14% versus 6%), diarrhea (11% versus 6%), decreased appetite (14% versus 0%), and anxiety (11% versus 0%). CONCLUSIONS: At doses of 150-300 mg/day, JZP-110 was well tolerated and significantly improved the ability to stay awake and subjective symptoms of excessive sleepiness in adults with narcolepsy. CLINICAL TRIALS REGISTRATION: Clinicaltrials.gov identifier NCT01681121.
Asunto(s)
Carbamatos/uso terapéutico , Narcolepsia/tratamiento farmacológico , Fenilalanina/análogos & derivados , Promotores de la Vigilia/uso terapéutico , Adulto , Anciano , Carbamatos/farmacología , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Narcolepsia/fisiopatología , Fenilalanina/farmacología , Fenilalanina/uso terapéutico , Fases del Sueño/efectos de los fármacos , Resultado del Tratamiento , Vigilia/efectos de los fármacos , Promotores de la Vigilia/farmacologíaRESUMEN
BACKGROUND: JZP-110 is a wake-promoting agent with dopaminergic and noradrenergic activity. METHODS: This double-blind, crossover study, randomized adults with narcolepsy with or without cataplexy (N = 33) to placebo or JZP-110 at 150 mg/day (weeks 1 and 3) increased to 300 mg/day (weeks 2 and 4). Patients had to have baseline Epworth Sleepiness Scale (ESS) scores ≥10 and mean sleep latencies ≤10 min on the Maintenance of Wakefulness Test (MWT). Efficacy end points included MWT sleep latency and ESS, and the percentage of patients improved on the Clinical Global Impression of Change. RESULTS: Patients were primarily male (57.6%) and white (69.7%), with a mean (standard deviation) age of 37.1 (12.4) years. At two weeks, the change in the mean MWT sleep latency was 11.8 min longer with JZP-110 than with placebo (P = 0.0002); JZP-110 resulted in greater changes in sleep latency on each MWT trial (P <0.001). For ESS, JZP-110 was more efficacious relative to placebo after 1 (P <0.0001) and two weeks (P = 0.0002); final ESS scores were 10.8 with JZP-110 and 15.2 with placebo, changes of -6.7 and -2.4, respectively. JZP-110 was generally well tolerated; the most common adverse events with JZP-110 were nausea (12%), noncardiac chest discomfort (9.1%), and headache (9.1%). CONCLUSIONS: The efficacy of JZP-110 for impaired wakefulness and excessive sleepiness was observed at 150-300 mg/day and as early as one week after initiating treatment (Clinicaltrials.gov identifier NCT01485770).
Asunto(s)
Narcolepsia/tratamiento farmacológico , Fenilalanina/análogos & derivados , Fenilalanina/uso terapéutico , Administración Oral , Adulto , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Narcolepsia/complicaciones , Narcolepsia/fisiopatología , Resultado del Tratamiento , Vigilia/efectos de los fármacosRESUMEN
OBJECTIVE: To determine the stability of improvement in polysomnographic measures of sleep disordered breathing, patient reported outcomes, the durability of hypoglossal nerve recruitment and safety at 18 months in the Stimulation Treatment for Apnea Reduction (STAR) trial participants. DESIGN: Prospective multicenter single group trial with participants serving as their own controls. SETTING: Twenty-two community and academic sleep medicine and otolaryngology practices. MEASUREMENTS: Primary outcome measures were the apnea-hypopnea index (AHI) and the 4% oxygen desaturation index (ODI). Secondary outcome measures were the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire (FOSQ), and oxygen saturation percent time < 90% during sleep. Stimulation level for each participant was collected at three predefined thresholds during awake testing. Procedure- and/or device-related adverse events were reviewed and coded by the Clinical Events Committee. RESULTS: The median AHI was reduced by 67.4% from the baseline of 29.3 to 9.7/h at 18 mo. The median ODI was reduced by 67.5% from 25.4 to 8.6/h at 18 mo. The FOSQ and ESS improved significantly at 18 mo compared to baseline values. The functional threshold was unchanged from baseline at 18 mo. Two participants experienced a serious device-related adverse event requiring neurostimulator repositioning and fixation. No tongue weakness reported at 18 mo. CONCLUSION: Upper airway stimulation via the hypoglossal nerve maintained a durable effect of improving airway stability during sleep and improved patient reported outcomes (Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire) without an increase of the stimulation thresholds or tongue injury at 18 mo of follow-up.
Asunto(s)
Sistema Respiratorio , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Nervio Hipogloso/fisiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sueño/fisiología , Síndromes de la Apnea del Sueño/fisiopatología , Síndromes de la Apnea del Sueño/terapia , Encuestas y Cuestionarios , Factores de Tiempo , Lengua/fisiología , VigiliaRESUMEN
BACKGROUND: Obstructive sleep apnea is associated with considerable health risks. Although continuous positive airway pressure (CPAP) can mitigate these risks, effectiveness can be reduced by inadequate adherence to treatment. We evaluated the clinical safety and effectiveness of upper-airway stimulation at 12 months for the treatment of moderate-to-severe obstructive sleep apnea. METHODS: Using a multicenter, prospective, single-group, cohort design, we surgically implanted an upper-airway stimulation device in patients with obstructive sleep apnea who had difficulty either accepting or adhering to CPAP therapy. The primary outcome measures were the apnea-hypopnea index (AHI; the number of apnea or hypopnea events per hour, with a score of ≥15 indicating moderate-to-severe apnea) and the oxygen desaturation index (ODI; the number of times per hour of sleep that the blood oxygen level drops by ≥4 percentage points from baseline). Secondary outcome measures were the Epworth Sleepiness Scale, the Functional Outcomes of Sleep Questionnaire (FOSQ), and the percentage of sleep time with the oxygen saturation less than 90%. Consecutive participants with a response were included in a randomized, controlled therapy-withdrawal trial. RESULTS: The study included 126 participants; 83% were men. The mean age was 54.5 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 28.4. The median AHI score at 12 months decreased 68%, from 29.3 events per hour to 9.0 events per hour (P<0.001); the ODI score decreased 70%, from 25.4 events per hour to 7.4 events per hour (P<0.001). Secondary outcome measures showed a reduction in the effects of sleep apnea and improved quality of life. In the randomized phase, the mean AHI score did not differ significantly from the 12-month score in the nonrandomized phase among the 23 participants in the therapy-maintenance group (8.9 and 7.2 events per hour, respectively); the AHI score was significantly higher (indicating more severe apnea) among the 23 participants in the therapy-withdrawal group (25.8 vs. 7.6 events per hour, P<0.001). The ODI results followed a similar pattern. The rate of procedure-related serious adverse events was less than 2%. CONCLUSIONS: In this uncontrolled cohort study, upper-airway stimulation led to significant improvements in objective and subjective measurements of the severity of obstructive sleep apnea. (Funded by Inspire Medical Systems; STAR ClinicalTrials.gov number, NCT01161420.).
Asunto(s)
Terapia por Estimulación Eléctrica , Nervio Hipogloso , Apnea Obstructiva del Sueño/terapia , Adulto , Anciano , Terapia por Estimulación Eléctrica/efectos adversos , Femenino , Humanos , Pulmón , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Músculos Faríngeos/inervación , Músculos Faríngeos/fisiopatología , Polisomnografía , Estudios ProspectivosRESUMEN
BACKGROUND: The ability to control impulses varies greatly, and difficulty with impulse control can have severe consequences; in the extreme, it is the defining feature of many psychiatric disorders. Evidence from disparate lines of research suggests that uric acid is elevated in psychiatric disorders characterized by high impulsivity, such as attention-deficit/hyperactivity disorder and bipolar disorder. The present research tests the hypothesis that impulsivity is associated with higher uric acid in humans and mice. METHODS: Using two longitudinal, nonclinical community samples (total n = 6883), we tested whether there is an association between uric acid and normal variation in trait impulsivity measured with the Revised NEO Personality Inventory. We also examined the effect of uric acid on behavior by comparing wild-type mice, which naturally have low levels of uric acid, with mice genetically modified to accumulate high levels of uric acid. RESULTS: In both human samples, the emotional aspects of trait impulsivity, specifically impulsiveness and excitement seeking, were associated with higher levels of uric acid concurrently and when uric acid was measured 3 to 5 years later. Consistent with the human data, the genetically modified mice displayed significantly more exploratory and novelty-seeking behavior than the wild-type mice. CONCLUSIONS: Higher uric acid was associated with impulsivity in both humans and mice. The identification of biological markers of impulsivity may lead to a better understanding of the physiological mechanisms involved in impulsivity and may suggest potential targets for therapeutic intervention.
Asunto(s)
Conducta Impulsiva/sangre , Ácido Úrico/sangre , Adulto , Anciano , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Femenino , Humanos , Conducta Impulsiva/epidemiología , Conducta Impulsiva/fisiopatología , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos Mentales/epidemiología , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Inventario de Personalidad , Factores de Tiempo , Urato Oxidasa/deficiencia , Urato Oxidasa/genéticaRESUMEN
STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with an increased risk of motor vehicle crashes. This driving risk can be reduced (≥ 50%) by treatment with continuous positive airway pressure (CPAP). However residual excessive daytime sleepiness (EDS) can persist for some patients who regularly use CPAP. The current study was designed to assess the effect of armodafinil on simulated driving performance and subsequent CPAP treatment compliance in newly diagnosed OSA patients with EDS during a 2-week "waiting period" prior to initiation of CPAP. METHODS: Sixty-nine newly diagnosed OSA patients, awaiting CPAP therapy, were randomized (1:1) to placebo or armodafinil (150 mg/day) treatment. Simulated driving tests and self-report measures were completed at baseline, after 2 weeks of drug treatment, and following 6 weeks of CPAP treatment. CPAP compliance was evaluated at the end of 6 weeks of CPAP. RESULTS: Compared to placebo, armodafinil improved simulated driving safety performance in OSA patients awaiting CPAP therapy (p = 0.03). Improvement was seen in lane position deviation (p = 0.002) and number of lane excursions (p = 0.02). Improvement was also observed on measures of sleepiness using the Epworth Sleepiness Scale (ESS) and sleep related quality of life. Following 6 weeks of CPAP, there was also significant improvement observed on multiple measures of simulated driving performance. CPAP compliance did not differ between armodafinil-treated and placebo-treated patients (p = 0.80). CONCLUSIONS: Armodafinil was found to improve simulated driving performance in OSA patients with EDS prior to initiation of CPAP. Treatment with armodafinil showed no effect on subsequent CPAP compliance.
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Conducción de Automóvil/estadística & datos numéricos , Compuestos de Bencidrilo/farmacología , Presión de las Vías Aéreas Positiva Contínua/métodos , Apnea Obstructiva del Sueño/terapia , Promotores de la Vigilia/farmacología , Adulto , Simulación por Computador , Método Doble Ciego , Femenino , Humanos , Masculino , Modafinilo , Cooperación del Paciente/estadística & datos numéricos , Desempeño Psicomotor/efectos de los fármacos , Autoinforme , Resultado del Tratamiento , Vigilia/efectos de los fármacosRESUMEN
Recent findings suggest that neurons can efficiently repair oxidatively damaged DNA, and that both DNA damage and repair are enhanced by activation of excitatory glutamate receptors. However, in pathological conditions such as ischemic stroke, excessive DNA damage can trigger the death of neurons. Oxidative DNA damage is mainly repaired by base excision repair (BER), a process initiated by DNA glycosylases that recognize and remove damaged DNA bases. Endonuclease VIII-like 1 (NEIL1) is a DNA glycosylase that recognizes a broad range of oxidative lesions. Here, we show that mice lacking NEIL1 exhibit impaired memory retention in a water maze test, but no abnormalities in tests of motor performance, anxiety, or fear conditioning. NEIL1 deficiency results in increased brain damage and a defective functional outcome in a focal ischemia/reperfusion model of stroke. The incision capacity on a 5-hydroxyuracil-containing bubble substrate was lower in the ipsilateral side of ischemic brains and in the mitochondrial lysates of unstressed old NEIL1-deficient mice. These results indicate that NEIL1 plays an important role in learning and memory and in protection of neurons against ischemic injury.
Asunto(s)
Isquemia Encefálica/metabolismo , Daño del ADN/fisiología , ADN Glicosilasas/fisiología , Reparación del ADN/fisiología , Memoria a Corto Plazo/fisiología , Orientación/fisiología , Análisis de Varianza , Animales , Isquemia Encefálica/patología , ADN Glicosilasas/deficiencia , ADN Glicosilasas/metabolismo , Reparación del ADN/genética , Etiquetado Corte-Fin in Situ , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Noqueados , Microscopía Fluorescente , Estadísticas no ParamétricasRESUMEN
Alzheimer's disease (AD) is an incurable and progressive neurodegenerative senile disorder associated with the brain accumulation of Aß plaques. Although vaccines that reduce Aß plaques can control AD, the rationale for their use at the onset of the disease remains debatable. Old humans and mice usually respond poorly to vaccines due to presumably age-related immunological impairments. Here, we report that by modifying vaccines, the poor responsiveness of old mice can be reversed. Unlike the Aß peptide vaccine, DNA immunizations with the amino-terminal Aß(1-11) fragment exposed on the surface of HBsAg particles elicit high levels of anti-Aß antibody both in young and old mice. Importantly, in AD model 3xTgAD mice, the vaccine reduced Aß plaques, ameliorated cognitive impairments and, surprisingly, significantly increased life span. Hence, we propose that vaccines targeting Aß(1-11) can efficiently combat AD-induced pathological alterations and provide survival benefit in patients with AD.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Vacunas contra el Alzheimer/inmunología , Péptidos beta-Amiloides/inmunología , Epítopos de Linfocito B/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Fragmentos de Péptidos/inmunología , Factores de Edad , Enfermedad de Alzheimer/inmunología , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Linfocitos T/inmunología , Vacunas de ADN/inmunologíaAsunto(s)
Causas de Muerte , Vigilancia de Productos Comercializados/métodos , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Oxibato de Sodio/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/mortalidad , Femenino , Humanos , Masculino , Estudios Retrospectivos , Sensibilidad y Especificidad , Trastornos del Sueño-Vigilia/diagnóstico , Oxibato de Sodio/farmacología , Oxibato de Sodio/uso terapéutico , Análisis de Supervivencia , Estados UnidosRESUMEN
PURPOSE: Sodium oxybate (SXB) is approved for cataplexy and excessive daytime sleepiness in narcolepsy. Obstructive sleep apnea syndrome (OSAS) affects â¼9-50% of narcoleptics. Effects of 2-week SXB administration on apnea-hypopnea index (AHI), oxygen saturation (SaO(2)), and sleep architecture were investigated in OSAS patients. METHODS: OSAS patients (n = 48) received 2-week SXB or placebo (PBO) treatment with polysomnography at baseline and day 14. The primary outcome measure was change from baseline in mean AHI. Secondary outcomes included changes from baseline in SaO(2), and sleep architecture. RESULTS: Compared with PBO, SXB significantly increased reduction in mean AHI and obstructive apnea index with SXB (-0.8 ± 13.3 vs. -8.2 ± 10.0; p = 0.0327 and 3.54 ± 11.1 vs. -4.72 ± 7.7; p = 0.0054, respectively) and significantly increased change in slow wave sleep duration (5.2 ± 25.0 min vs. 29.4 ± 37.0 min; p = 0.0038). There were no differences between treatments in SaO2, central apneic events, or other measures. Adverse events, most commonly headache, were noted in nine of 27 (33%) and six of 23 (26%) patients receiving SXB and PBO, respectively. CONCLUSIONS: Short-term use of 4.5 g/night SXB did not generate respiratory depressant effects in OSAS patients as measured by AHI, obstructive apnea events, central apneas, and SaO2. Extended use of SXB in higher therapeutic doses in OSAS has not been studied, and merits caution.
Asunto(s)
Adyuvantes Anestésicos/uso terapéutico , Polisomnografía/efectos de los fármacos , Apnea Obstructiva del Sueño/tratamiento farmacológico , Oxibato de Sodio/uso terapéutico , Adyuvantes Anestésicos/efectos adversos , Adulto , Compuestos de Bencidrilo/efectos adversos , Compuestos de Bencidrilo/uso terapéutico , Estimulantes del Sistema Nervioso Central/efectos adversos , Estimulantes del Sistema Nervioso Central/uso terapéutico , Terapia Combinada , Presión de las Vías Aéreas Positiva Contínua , Trastornos de Somnolencia Excesiva/tratamiento farmacológico , Quimioterapia Combinada , Femenino , Humanos , Hipnóticos y Sedantes/efectos adversos , Hipnóticos y Sedantes/uso terapéutico , Masculino , Persona de Mediana Edad , Modafinilo , Piridinas/efectos adversos , Piridinas/uso terapéutico , Oxibato de Sodio/efectos adversos , ZolpidemRESUMEN
PURPOSE: While the symptoms of narcolepsy are often amenable to treatment with sodium oxybate (SXB), the respiratory effects of long-term SXB treatment have not been systematically studied. Recent reports have implicated SXB with several cases of worsening sleep-related breathing disturbances and accidental death. In addition, these patients are at risk for obesity, which may aggravate co-morbid obstructive sleep apnea. METHODS: Based on a review of the literature and the clinical experience of the author, recommendations for the use of SXB in patients with sleep-disordered breathing have been developed. RESULTS: Among narcolepsy patients with evidence of sleep disordered breathing during baseline polysomnography, SXB should be prescribed only to those patients who fully comply with nasal continuous positive airway pressure therapy. The respiratory status of other SXB-treated patients should be periodically evaluated with nocturnal oximetry. CONCLUSIONS: Based on the currently available data, physicians prescribing SXB should remain vigilant for the possible development of sleep-disordered breathing during long-term treatment with SXB.
Asunto(s)
Adyuvantes Anestésicos/uso terapéutico , Monitoreo de Drogas , Narcolepsia/tratamiento farmacológico , Síndromes de la Apnea del Sueño/prevención & control , Oxibato de Sodio/uso terapéutico , Adyuvantes Anestésicos/efectos adversos , Humanos , Narcolepsia/diagnóstico , Síndromes de la Apnea del Sueño/diagnóstico , Sueño REM/efectos de los fármacos , Oxibato de Sodio/efectos adversosRESUMEN
OBJECTIVE: Sodium oxybate (SXB) is an approved drug for the treatment of excessive daytime sleepiness (EDS) and cataplexy in narcolepsy. Obstructive sleep apnea syndrome (OSAS) is a condition that frequently co-occurs with narcolepsy. Given the known central nervous system (CNS) depressant effects of SXB, this study aimed to examine its effects on sleep-disordered breathing (SDB) and sleep architecture in patients with OSAS. METHODS: Sixty patients with a history of mild to moderate OSAS (apnea-hypopnea index [AHI]>or=10 and
Asunto(s)
Adyuvantes Anestésicos/efectos adversos , Compuestos de Bencidrilo/efectos adversos , Estimulantes del Sistema Nervioso Central/efectos adversos , Hipnóticos y Sedantes/efectos adversos , Polisomnografía/efectos de los fármacos , Piridinas/efectos adversos , Apnea Obstructiva del Sueño/tratamiento farmacológico , Oxibato de Sodio/efectos adversos , Adyuvantes Anestésicos/uso terapéutico , Adulto , Anciano , Compuestos de Bencidrilo/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Comorbilidad , Presión de las Vías Aéreas Positiva Contínua , Estudios Cruzados , Método Doble Ciego , Quimioterapia Combinada , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Hipnóticos y Sedantes/uso terapéutico , Masculino , Persona de Mediana Edad , Modafinilo , Narcolepsia/tratamiento farmacológico , Narcolepsia/epidemiología , Oxígeno/sangre , Vigilancia de Productos Comercializados , Piridinas/uso terapéutico , Apnea Obstructiva del Sueño/epidemiología , Fases del Sueño/efectos de los fármacos , Oxibato de Sodio/uso terapéutico , ZolpidemRESUMEN
OBJECTIVES: Evaluate efficacy and safety of the histamine-H1 antagonist doxepin at doses of 1 mg, 3 mg, and 6 mg in elderly adults with primary insomnia. DESIGN: A randomized, double-blind, placebo-controlled, crossover design was used in this population of elderly adults with primary insomnia (DSM-IV). Each treatment period consisted of 2 polysomnographic (PSG) assessment nights with a 5- or 12-day drug-free interval between periods. The study was conducted from September 2004 to January 2005. SETTING: Sleep laboratories in 11 sleep centers in the United States. PARTICIPANTS: Elderly adults with primary insomnia. INTERVENTION: Doxepin 1 mg, 3 mg, and 6 mg. MEASUREMENTS: Efficacy was assessed using PSG and patient-reported measures. RESULTS: Seventy-six patients were randomly assigned. All 3 doxepin doses produced dose-related significant improvements in PSG-determined wake time during sleep (p < .0001), wake time after sleep onset (p < .0001), total sleep time (p < .0001), and overall sleep efficiency (p < .0001) versus placebo. At the 3-mg and 6-mg doses, sleep efficiency was significantly improved during all thirds of the night (p < .05). There was a dose-related decrease in patient-reported sleep latency, with the 6-mg dose achieving statistical significance in latency to sleep onset (p = .0181). The pattern of the remaining subjective efficacy results was consistent with PSG. All 3 doxepin doses had side effect profiles comparable to placebo, with no spontaneously reported anticholinergic effects, no memory impairment, and no significant next-day residual effects. CONCLUSIONS: In this 2-night study of elderly adults with primary insomnia, doxepin doses of 1 mg, 3 mg, and 6 mg were well tolerated and produced significant improvement in objective and subjective sleep maintenance and duration endpoints that persisted into the final hour of the night. Positive effects on patient-reported sleep onset were observed at the highest dose. All 3 doxepin doses had a safety profile comparable to placebo. These data demonstrate that doxepin was efficacious in improving sleep in elderly adults.
Asunto(s)
Doxepina/administración & dosificación , Antagonistas de los Receptores Histamínicos/administración & dosificación , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Anciano , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Doxepina/efectos adversos , Doxepina/farmacología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Antagonistas de los Receptores Histamínicos/efectos adversos , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Masculino , Polisomnografía , Fases del Sueño/efectos de los fármacos , Estados UnidosRESUMEN
Excessive sleepiness associated with narcolepsy lasts throughout the waking day. The authors conducted two randomized, double-blind studies to compare the efficacy of modafinil once-daily versus split doses in maintaining wakefulness throughout the day. Fifty-six patients received modafinil. The split-dose regimens were significantly more effective than the 200-mg once-daily regimen for sustaining wakefulness in the late afternoon/evening. All modafinil dosing regimens were well tolerated. In patients who experience excessive sleepiness in the late afternoon/evening, despite satisfactory treatment earlier in the day, a split dose of modafinil may promote wakefulness throughout the waking day.
Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Narcolepsia/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Vigilia/efectos de los fármacos , Adolescente , Adulto , Anciano , Demografía , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modafinilo , Narcolepsia/etiología , Neoplasia Residual/complicaciones , Tiempo de ReacciónRESUMEN
INTRODUCTION: In addition to excessive sleepiness, patients with narcolepsy often have significant fatigue, depressed mood, and decreased quality of life. OBJECTIVE: To determine whether treatment with modafinil for excessive sleepiness improves fatigue, mood, and health-related quality of life (HRQOL) in patients with narcolepsy. MATERIALS AND METHODS: Outpatients with narcolepsy underwent a 14-day washout of psychostimulants and then were enrolled in this 6-week, open-label, multicenter study. Patients received modafinil starting at 200 mg once daily for week 1, and then 200 or 400 mg daily for weeks 2 through 6. Efficacy was evaluated using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Profile of Mood States (POMS). Safety was assessed by monitoring adverse events (AE). RESULTS: At baseline, 151 patients had moderate to severe excessive sleepiness (mean Epworth Sleepiness Scale score=17.8+/-4.4). Most patients (> or =70% of 123 who completed the study) received 400 mg modafinil once daily during weeks 2 through 6. Modafinil significantly improved HRQOL, based on SF-36 measures of mental and physical component summary scores and subdomain scores of role-physical, social functioning, and vitality (each P<0.001). Modafinil treatment was also associated with significantly reduced fatigue and significantly improved vigor and cognition as assessed by the POMS (each P<0.001) from weeks 1 through 6. The most frequent AE with modafinil treatment were headache, nausea, and insomnia; most AE were mild or moderate in nature. Only seven patients (5%) withdrew from the study because of AE. CONCLUSION: In narcolepsy patients who were switched from psychostimulants, modafinil therapy improved HRQOL and subjective feelings of vigor and cognitive functioning and reduced fatigue.