Infusion of sodium DL-3-ß-hydroxybutyrate decreases cerebral injury biomarkers after resuscitation in experimental cardiac arrest.

AIMS: Cerebral complications after cardiac arrest (CA) remain a major problem worldwide. The aim was to test the effects of sodium-ß-hydroxybutyrate (SBHB) infusion on brain injury in a clinically relevant swine model of CA. RESULTS: CA was electrically induced in 20 adult swine. After 10 min, cardiopulmonary resuscitation was performed for 5 min. After return of spontaneous circulation (ROSC), the animals were randomly assigned to receive an infusion of balanced crystalloid (controls, n = 11) or SBHB (theoretical osmolarity 1189 mOsm/l, n = 8) for 12 h. Multimodal neurological and cardiovascular monitoring were implemented in all animals. Nineteen of the 20 animals achieved ROSC. Blood sodium concentrations, osmolarity and circulating KBs were higher in the treated animals than in the controls. SBHB infusion was associated with significantly lower plasma biomarkers of brain injury at 6 (glial fibrillary acid protein, GFAP and neuron specific enolase, NSE) and 12 h (neurofilament light chain, NFL, GFAP and NSE) compared to controls. The amplitude of the stereoelectroencephalograph (sEEG) increased in treated animals after ROSC compared to controls. Cerebral glucose uptake was lower in treated animals. CONCLUSIONS: In this experimental model, SBHB infusion after resuscitated CA was associated with reduced circulating markers of cerebral injury and increased sEEG amplitude.

Improvements in daytime sleepiness and disrupted nighttime sleep with once-nightly sodium oxybate in people with narcolepsy type 1 and type 2: a plain language summary.

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.

Use of sodium oxybate for the treatment of alcohol withdrawal syndrome in patients with acute alcohol-associated hepatitis: A 4-patient case report.

INTRODUCTION: During the treatment of alcohol use disorder, alcohol withdrawal syndrome (AWS) can occur. Benzodiazepines remain the "gold standard" for the pharmacological treatment of AWS. However, other drugs have been approved in some European Countries for the treatment of AWS: namely, clomethiazole in Spain and Germany and sodium oxybate in Italy and Austria. Acute alcohol-associated hepatitis (AAH) is a distinct clinical syndrome characterized by the recent onset of jaundice with or without other signs of liver decompensation in patients with ongoing alcohol consumption. RATIONALE: We report 4 paradigmatic clinical cases to analyze the efficacy, safety, and tolerability of the very short half-life (30-45 minutes) sodium oxybate (SO) in the management of AWS with moderate to severe AAH. Compared to SO, "as needed" short-acting benzodiazepines, currently prescribed to treat AWS in patients with AAH, have a much longer half-life (5-25 hours) which increases the risk of drug accumulation. The very short half-life of SO provides a fixed dose approach allowing for a more effective control of AWS than "as needed" therapy throughout the 24 hours. PATIENT CONCERNS: Patients reported anxiety, agitation, diffuse abdominal pain, loss of appetite, and nausea with elevation in serum bilirubin and 2 of them had abdomen distension due to ascites. DIAGNOSIS: Patients were affected by moderate or severe AWS and moderate or severe AAH on alcohol-related liver cirrhosis. INTERVENTIONS: In order to suppress AWS, all patients were treated with oral sodium oxybate at a dose of 25 mg/kg/day, progressively increased to 50 to 100 mg/kg/day, divided into 3 to 5 administrations. OUTCOMES: SO was efficient, safe and tolerable in suppressing AWS even in patients with severe AAH. All treated patients showed a rapid improvement of all symptom (via the Clinical Institute of Withdrawal Assessment for Alcohol Scale) and liver test scores (Model for End-Stage Liver Disease). CONCLUSION: Because of its short half-life, SO can be considered a safe and effective pharmacological option for the AWS in patients with moderate to severe AAH even in comparison to short-acting benzodiazepines, thus avoiding the risk of accumulation. Notably, SO guarantees a fixed approach to cover the possible onset of AWS throughout the 24 hours.

Clinical considerations in the treatment of idiopathic hypersomnia.

Idiopathic hypersomnia typically is a chronic and potentially debilitating neurologic sleep disorder, and is characterized by excessive daytime sleepiness. In addition to excessive daytime sleepiness, idiopathic hypersomnia symptoms can include severe sleep inertia; long, unrefreshing naps; long sleep time; and cognitive dysfunction. Patients with idiopathic hypersomnia may experience a significant impact on their quality of life, work or school performance, earnings, employment, and overall health. Given the complex range of symptoms associated with idiopathic hypersomnia and the array of treatments available, there is a need to provide guidance on the treatment of idiopathic hypersomnia and the clinically relevant recommendations that enhance effective disease management. Identifying appropriate treatment options for idiopathic hypersomnia requires timely and accurate diagnosis, consideration of individual patient factors, and frequent reassessment of symptom severity. In 2021, low-sodium oxybate was the first treatment to receive approval by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults. However, many off-label treatments continue to be used. Adjunct nonpharmacologic therapies, including good sleep hygiene, patient education and counseling, and use of support groups, should be recognized and recommended when appropriate. This narrative review describes optimal treatment strategies that take into account patient-specific factors, as well as the unique characteristics of each medication and the evolution of a patient's response to treatment. Perspectives on appropriate symptom measurement and management, and potential future therapies, are also offered.

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.

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.

Repurposing drugs for treatment of alcohol use disorder.

Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.

Sleep-related painful erections treated with sodium oxybate.

A 39-year-old male with a medical history significant for migraine, psoriatic arthritis, postural orthostatic tachycardia syndrome, vitamin D deficiency, and hypoglycemia presented with a 2-year history of sleep-related painful erections. Because the reported prevalence is low, there is limited understanding of the possible etiologies of the disorder and few published clinical data on treatment algorithms. Thus, he had tried multiple therapies. Baclofen was effective but not tolerated. Pelvic physiotherapy and tadalafil were ineffective. Imipramine, clonazepam, vitamin B, iron, and selenium provided minimal benefit. Opiates were initially effective but lost efficacy after 2-3 weeks. Finally, he was started on sodium oxybate after fully counseling the patient on the potential side effects of the treatment and consenting the patient for off-label use. This has effectively treated his sleep-related painful erections. Sodium oxybate is a novel therapy for and a possible new treatment for this rare and challenging disorder that merits further study. CITATION: Chaudhary HS, Zeidman E, Punjani N, Tashman Y. Sleep-related painful erections treated with sodium oxybate. J Clin Sleep Med. 2024;20(7):1209-1211.

Effects of intraoperative sodium oxybate infusion on post-operative sleep quality in patients undergoing gynecological laparoscopic surgery: A randomized clinical trial.

STUDY OBJECTIVE: Post-operative sleep quality is an important factor that influences post-operative recovery. Sodium oxybate has been used to treat sleep disturbances associated with various pathological conditions. However, whether intraoperative intravenous infusion of sodium oxybate improves post-operative sleep quality is unknown. This study aimed to examine the effects of sodium oxybate on the post-operative sleep quality of patients who underwent gynecological laparoscopic surgery. DESIGN: A single-center, prospective, two-arm, double-blinded randomized controlled trial. SETTING: The Shengjing Hospital of China Medical University in Liaoning, China. PATIENTS: We enrolled 180 adult patients (90 for each group) undergoing elective gynecological laparoscopic surgery, and 178 patients (89 for each group) were included in the final analysis. INTERVENTIONS: Patients were randomly allocated in a 1:1 ratio to receive either sodium oxybate (30 mg kg-1) or an equivalent volume of saline after intubation. The patients, anesthetists, and follow-up staff were blinded to group assignment. MEASUREMENTS: The primary outcome was sleep quality measured using the Richards-Campbell Sleep Questionnaire (RCSQ) on post-operative days (PODs) one and three. Secondary outcomes included post-operative pain measured using the visual analog scale, sleep quality at one and three months post-operatively measured using the Pittsburgh Sleep Quality Index, and factors associated with post-operative sleep quality. MAIN RESULTS: Analysis with generalized estimating equations showed that sodium oxybate significantly improved post-operative sleep quality, as represented by increased total RCSQ scores (mean difference (95% CI); 9 (2, 16), P = 0.010) over PODs one and three. There was no difference in post-operative pain between the two groups over PODs one and three or in post-operative sleep quality over one and three months post-operatively. Age, surgery type, start time of surgery, and use of sufentanil-based patient-controlled intravenous analgesia were significantly associated with post-operative sleep quality. CONCLUSIONS: Intraoperative sodium oxybate infusion improved post-operative sleep in patients who underwent gynecological laparoscopic surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry, Clinical trial number: ChiCTR2200061460.

Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy.

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.

Once-nightly sodium oxybate (FT218) improved symptoms of disrupted nighttime sleep in people with narcolepsy: a plain language summary.

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.

[Multidrug resistant narcolepsy]. / Narcolepsia multirresistente.

INTRODUCTION: Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical manifestations, both in wakefulness and in sleep. The symptoms are often so disruptive that they cause enormous suffering and impair patients' quality of life. Although a non-pharmacological approach is sometimes sufficient, the vast majority of patients need medication for adequate clinical management. CASE REPORT: A male who, at 43 years of age, began to present acutely with excessive daytime sleepiness and episodes of cataplexy. After a thorough examination, he was diagnosed with narcolepsy type 1. Throughout the course of the disease, he was prescribed antidepressants, neurostimulants and sodium oxybate, in monotherapy or in combination. The response to pharmacological treatment was insufficient and accompanied by numerous side effects. Following the introduction of pitolisant, there was a marked improvement in his symptoms and a reduction in the dose of the other drugs and their adverse effects was achieved. CONCLUSION: A number of measures are now available to address the cardinal symptoms of the disease, although there are still cases that are resistant to anti-narcoleptic treatment. Drugs with mechanisms of action that act upon receptors in the histaminergic system can be very useful in these cases.

TITLE: Narcolepsia multirresistente.Introducción. La narcolepsia de tipo 1 es una enfermedad degenerativa focal del hipotálamo que afecta selectivamente a las neuronas productoras de orexina (hipocretina). Presenta múltiples manifestaciones clínicas, tanto en vigilia como en sueño. Con frecuencia, los síntomas son tan disruptivos que ocasionan enorme sufrimiento y deterioro de la calidad de vida de los pacientes. Aunque en ocasiones es suficiente con un abordaje no farmacológico, la gran mayoría de los enfermos necesita medicación para un adecuado control clínico. Caso clínico. Varón que a los 43 años comenzó a presentar de forma aguda excesiva somnolencia diurna y episodios de cataplejía. Tras un exhaustivo estudio se le diagnosticó narcolepsia de tipo 1. A lo largo de la evolución de la enfermedad se le prescribieron antidepresivos, neuroestimulantes y oxibato sódico, en monoterapia o en combinación. La respuesta al tratamiento farmacológico fue insuficiente y se acompañó de numerosos efectos secundarios. Tras la introducción de pitolisant se objetivó una franca mejoría de los síntomas, y se consiguió reducir la dosis de los otros fármacos y de sus efectos adversos. Conclusión. Son numerosas las medidas disponibles en la actualidad para abordar los síntomas cardinales de la enfermedad, aunque siguen existiendo casos resistentes al tratamiento antinarcoléptico. Los fármacos con mecanismos de acción sobre receptores del sistema histaminérgico pueden resultar de gran utilidad en estos casos.

Efficacy of once-nightly sodium oxybate (FT218) in narcolepsy type 1 and type 2: post hoc analysis from the Phase 3 REST-ON Trial.

STUDY OBJECTIVES: Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2). METHODS: Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 4-8; and 9 g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups. RESULTS: The modified intent-to-treat population comprised 190 participants (NT1, n = 145; NT2, n = 45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, p < .001) and NT2 (6 and 9 g, p < .05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, p < .001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (p < .001), nocturnal arousals (p < .05), and ESS scores (p ≤ .001) were reported for NT1 with directional improvements for NT2. CONCLUSIONS: Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup.

Sodium oxybate in treatment-resistant rapid-eye-movement sleep behavior disorder.

STUDY OBJECTIVES: Symptomatic therapies for rapid-eye-movement (REM) sleep behavior disorder (RBD) are limited. Sodium oxybate (SXB), a gamma-aminobutyric acid (GABA)-B agonist, could be effective but has not been evaluated against placebo. METHODS: This double-blind, parallel-group, randomized, placebo-controlled trial in 24 participants was conducted at the Stanford Sleep Center. Patients were adults with definite iRBD or Parkinson's disease and probable RBD (PD-RBD), and persistence of ≥ 2 weekly episodes despite standard therapy. Patients were randomized 1:1 to receive SXB during a 4-week titration followed by a 4-week stable dosing period. Primary outcome was number of monthly RBD episodes according to a diary filled by patients and partners. Secondary outcomes were severity, number of severe RBD episodes, and objective RBD activity on video polysomnography. RESULTS: Twelve iRBD and 12 PD-RBD participated (mean 65.8 years), and 22 (n = 10 SXB, 12 placebo) completed the study. Although no significant between-group difference was found, SXB showed reduction of monthly RBD episodes by 23.1 (95% CI -36.0, -10.2; p = 0.001) versus 10.5 with placebo (95% CI, -22.6, 1.6; p = 0.087). Improvement from baseline was similarly observed for RBD overall severity burden (each episode weighted for severity), number of severe episodes, and objective RBD activity per video-polysomnography. Two participants receiving SXB withdrew due to anxiety and dizziness. The majority of adverse events are otherwise resolved with dose adjustment. CONCLUSION: SXB could reduce RBD symptoms; however, response was inconsistent and a large placebo effect was observed across patient-reported outcomes. Larger studies using objective endpoints are needed. CLINICAL TRIAL: Treatment of REM Sleep Behavior Disorder (RBD) With Sodium Oxybate https://clinicaltrials.gov/ct2/show/NCT04006925 ClinicalTrials.gov identifier: NCT04006925.

Nocturnal sodium oxybate increases the anterior cingulate cortex magnetic resonance glutamate signal upon awakening.

Clinical guidelines recommend sodium oxybate (SXB; the sodium salt of γ-hydroxybutyrate) for the treatment of disturbed sleep and excessive daytime sleepiness in narcolepsy, yet the underlying mode of action is elusive. In a randomised controlled trial in 20 healthy volunteers, we aimed at establishing neurochemical changes in the anterior cingulate cortex (ACC) following SXB-enhanced sleep. The ACC is a core neural hub regulating vigilance in humans. At 2:30 a.m., we administered in a double-blind cross-over manner an oral dose of 50 mg/kg SXB or placebo, to enhance electroencephalography-defined sleep intensity in the second half of nocturnal sleep (11:00 p.m. to 7:00 a.m.). Upon scheduled awakening, we assessed subjective sleepiness, tiredness and mood and measured two-dimensional, J-resolved, point-resolved magnetic resonance spectroscopy (PRESS) localisation at 3-Tesla field strength. Following brain scanning, we used validated tools to quantify psychomotor vigilance test (PVT) performance and executive functioning. We analysed the data with independent t tests, false discovery rate (FDR) corrected for multiple comparisons. The morning glutamate signal (at 8:30 a.m.) in the ACC was specifically increased after SXB-enhanced sleep in all participants in whom good-quality spectroscopy data were available (n = 16; pFDR < 0.002). Further, global vigilance (10th-90th inter-percentile range on the PVT) was improved (pFDR < 0.04) and median PVT response time was shorter (pFDR < 0.04) compared to placebo. The data indicate that elevated glutamate in the ACC could provide a neurochemical mechanism underlying SXB's pro-vigilant efficacy in disorders of hypersomnolence.

Phenobarbital to manage severe gamma-hydroxybutyrate withdrawal: A case series.

INTRODUCTION: Management of a withdrawal syndrome following cessation of regular gamma-hydroxybutyrate (GHB) use, and its precursors, can represent a clinical challenge due to rapid onset delirium and/or seizures. Severe GHB withdrawal can be characterised by persistent or worsening features despite increasing benzodiazepine doses and regular baclofen. Barbiturates, such as phenobarbital, are an appealing option in this context due to their unique GABA-A receptor action. CASE SERIES: This series describes the use of phenobarbital in 13 cases, 12 patients, across two hospitals in Sydney, Australia, with persistent or progressive GHB withdrawal despite benzodiazepine-based management. A median cumulative dose of oral diazepam prior to commencing phenobarbital was 120 mg (range 80-255 mg). The median time from the last GHB use to the first dose of phenobarbital was 24 h (range 7-57 h). Eight cases received phenobarbital orally on a general ward and 5 intravenously in intensive care units. An improvement in GHB withdrawal symptoms was observed after phenobarbital in all cases and there were no adverse events related to phenobarbital. DISCUSSION AND CONCLUSION: This case series suggests that phenobarbital for the management of benzodiazepine-resistant GHB withdrawal can be safe, even in general inpatient settings, and may avert the progression of delirium. Most data on the management of GHB withdrawal comes from case reports or series, such as this one. This highlights the need for prospective trials to establish an evidence base for therapeutic approaches, including validated measures of withdrawal severity and more information relating to the safe and effective dosing of phenobarbital.

The Treatment of Parkinson's Disease with Sodium Oxybate.

Sodiun Oxybate (SO) has a number of attributes that may mitigate the metabolic stress on the substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons in Parkinson's disease (PD). These neurons function at the borderline of energy sufficiency. SO is metabolized to succinate and supplies energy to the cell by generating ATP. SO is a GABAB agonist and, as such, also arrests the high energy requiring calcium pace-making activity of these neurons. In addition, blocking calcium entry impedes the synaptic release and subsequent neurotransmission of aggregated synuclein species. As DA neurons degenerate, a homeostatic failure exposes these neurons to glutamate excitotoxicity, which in turn accelerates the damage. SO inhibits the neuronal release of glutamate and blocks its agonistic actions. Most important, SO generates NADPH, the cell's major antioxidant cofactor. Excessive free radical production within DA neurons and even more so within activated microglia are early and key features of the degenerative process that are present long before the onset of motor symptoms. NADPH maintains cell glutathione levels and alleviates oxidative stress and its toxic consequences. SO, a histone deacetylase inhibitor also suppresses the expression of microglial NADPH oxidase, the major source of free radicals in Parkinson brain. The acute clinical use of SO at night has been shown to reduce daytime sleepiness and fatigue in patients with PD. With long-term use, its capacity to supply energy to DA neurons, impede synuclein transmission, block excitotoxicity and maintain an anti-oxidative redox environment throughout the night may delay the onset of PD and slow its progress.

Technical evaluation and usability of a quantitative G6PD POC test in cord blood: a mixed-methods study in a low-resource setting.

OBJECTIVES: New point-of-care (POC) quantitative G6PD testing devices developed to provide safe radical cure for Plasmodium vivax malaria may be used to diagnose G6PD deficiency in newborns at risk of severe neonatal hyperbilirubinaemia, improving clinical care, and preventing related morbidity and mortality. METHODS: We conducted a mixed-methods study analysing technical performance and usability of the 'STANDARD G6PD' Biosensor when used by trained midwives on cord blood samples at two rural clinics on the Thailand-Myanmar border. RESULTS: In 307 cord blood samples, the Biosensor had a sensitivity of 1.000 (95% CI: 0.859 to 1.000) and a specificity of 0.993 (95% CI: 0.971 to 0.999) as compared with gold-standard spectrophotometry to diagnose G6PD-deficient newborns using a receiver operating characteristic (ROC) analysis-derived threshold of ≤4.8 IU/gHb. The Biosensor had a sensitivity of 0.727 (95% CI: 0.498 to 0.893) and specificity of 0.933 (95% CI: 0.876 to 0.969) for 30%-70% activity range in girls using ROC analysis-derived range of 4.9-9.9 IU/gHb. These thresholds allowed identification of all G6PD-deficient neonates and 80% of female neonates with intermediate phenotypes.Need of phototherapy treatment for neonatal hyperbilirubinaemia was higher in neonates with deficient and intermediate phenotypes as diagnosed by either reference spectrophotometry or Biosensor.Focus group discussions found high levels of learnability, willingness, satisfaction and suitability for the Biosensor in this setting. The staff valued the capacity of the Biosensor to identify newborns with G6PD deficiency early ('We can know that early, we can counsel the parents about the chances of their children getting jaundice') and at the POC, including in more rural settings ('Because we can know the right result of the G6PD deficiency in a short time, especially for the clinic which does not have a lab'). CONCLUSIONS: The Biosensor is a suitable tool in this resource-constrained setting to identify newborns with abnormal G6PD phenotypes at increased risk of neonatal hyperbilirubinaemia.

Clinical features of different stage subacute combined degeneration of the spinal cord.

Subacute combined degeneration (SCD), caused by vitamin B12 disorders, leads to severe degeneration of the spinal cord. Thus, it is significant to make timely diagnosis and treatment options of SCD. The objectives were to summarize clinical features of different sate SCD. Clinical data of 42 SCD patients of spinal cord were retrospectively analyzed, which were classified into early stage, middle stage and late stage SCD. Among the patients, 9 were classified into early stage, 22 into middle stage, and 11 into late stage SCD. Total cholesterol and hemoglobin levels were relatively higher in late stage SCD. In contrast, mean corpusular volume (MCV) level was higher in early stage SCD. There were typical abnormalities only in 8 patients on magnetic resonance imaging (MRI), and a dynamia was a common neurological abnormality in all patients. Importantly, the differences in abnormal findings in anti-nuclear antibodies (ANA) testing, visual acuity and fundus testing were statistically significant in different stage SCD (P < .05). There were correlation between most variances with SCD stage. Strikingly, there existed close relationship between enhanced levels of blood glucose (r = -0.289, P = .066), glycated hemoglobin (GHB) (r = -0.288, P = .068) and homocysteine (r = -0.563, P = .000), abnormal visual findings (r = 0.309, P = .049) and megaloblastic anemia (r = -0.295, P = .061) with different SCD stage, among which abnormal visual findings were closely associated with middle stage SCD. Moreover, levels of total cholesterol, blood glucose, homocysteine and abnormal finding of visual acuity were significant in diagnosis and clinical staging of SCD (P < .05). Although MRI scanning and serum vitamin B12 level were widely used for SCD diagnosis, neurological examination and homocysteine level may be more potentially valuable indexes for SCD diagnosis and staging.