sodium-oxybate and Parkinson-Disease

Varying degrees of metabolic arrest are used by many living species to survive in a harsh environment. For example, in hibernating mammals, neuronal activity and cerebral metabolism are profoundly depressed in most regions of the brain and limited energy resources are deployed to maintain vital cell functions. Gathering evidence suggests that energy resources are also limited in both Alzheimer's and Parkinson's diseases, and that this promotes metabolic stress and the degenerative process. Key steps in this process are energy requiring, and this further compromises cell energy reserves. It may be possible to slow the progress of these diseases by inducing slow-wave sleep (SWS) at night with gammahydroxybutyrate. Patients with these diseases sleep poorly and generate little SWS. SWS and hibernation are thought to be on a continuum of energy conservation. Thus, the induction of SWS may retard the degenerative process by depressing cell metabolism and by directing energy utilization to vital cell functions. In this way, GHB-induced SWS may duplicate the effects of hibernation and extend biologic time.

Topics: Alzheimer Disease; Animals; Brain; Dementia; Energy Metabolism; Humans; Nerve Degeneration; Parkinson Disease; Sleep Stages; Sodium Oxybate

Sleep-wake disorders are a common and debilitating nonmotor manifestation of Parkinson disease (PD), but treatment options are scarce.. To determine whether nocturnal administration of sodium oxybate, a first-line treatment in narcolepsy, is effective and safe for excessive daytime sleepiness (EDS) and disturbed nighttime sleep in patients with PD.. Randomized, double-blind, placebo-controlled, crossover phase 2a study carried out between January 9, 2015, and February 24, 2017. In a single-center study in the sleep laboratory at the University Hospital Zurich, Zurich, Switzerland, 18 patients with PD and EDS (Epworth Sleepiness Scale [ESS] score >10) were screened in the sleep laboratory. Five patients were excluded owing to the polysomnographic diagnosis of sleep apnea and 1 patient withdrew consent. Thus, 12 patients were randomized to a treatment sequence (sodium oxybate followed by placebo or placebo followed by sodium oxybate, ratio 1:1) and, after dropout of 1 patient owing to an unrelated adverse event during the washout period, 11 patients completed the study. Two patients developed obstructive sleep apnea during sodium oxybate treatment (1 was the dropout) and were excluded from the per-protocol analysis (n = 10) but included in the intention-to-treat analysis (n = 12).. Nocturnal sodium oxybate and placebo taken at bedtime and 2.5 to 4.0 hours later with an individually titrated dose between 3.0 and 9.0 g per night for 6 weeks with a 2- to 4-week washout period interposed.. Primary outcome measure was change of objective EDS as electrophysiologically measured by mean sleep latency in the Multiple Sleep Latency Test. Secondary outcome measures included change of subjective EDS (ESS), sleep quality (Parkinson Disease Sleep Scale-2), and objective variables of nighttime sleep (polysomnography).. Among 12 patients in the intention-to-treat population (10 men, 2 women; mean [SD] age, 62 [11.1] years; disease duration, 8.4 [4.6] years), sodium oxybate substantially improved EDS as measured objectively (mean sleep latency, +2.9 minutes; 95% CI, 2.1 to 3.8 minutes; P = .002) and subjectively (ESS score, -4.2 points ; 95% CI, -5.3 to -3.0 points; P = .001). Thereby, 8 (67%) patients exhibited an electrophysiologically defined positive treatment response. Moreover, sodium oxybate significantly enhanced subjective sleep quality and objectively measured slow-wave sleep duration (+72.7 minutes; 95% CI, 55.7 to 89.7 minutes; P < .001). Differences were more pronounced in the per-protocol analysis. Sodium oxybate was generally well tolerated under dose adjustments (no treatment-related dropouts), but it induced de novo obstructive sleep apnea in 2 patients and parasomnia in 1 patient, as detected by polysomnography, all of whom did not benefit from sodium oxybate treatment.. This study provides class I evidence for the efficacy of sodium oxybate in treating EDS and nocturnal sleep disturbance in patients with PD. Special monitoring with follow-up polysomnography is necessary to rule out treatment-related complications and larger follow-up trials with longer treatment durations are warranted for validation.. clinicaltrials.gov Identifier: NCT02111122.

Topics: Adjuvants, Anesthesia; Aged; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Parkinson Disease; Polysomnography; Sleep Wake Disorders; Sodium Oxybate; Treatment Outcome

Many patients with Parkinson disease (PD) have excessive daytime sleepiness and numerous nocturnal sleep abnormalities.. To determine the safety and efficacy of the controlled drug sodium oxybate in a multicenter, open-label, polysomnographic study in subjects with PD and sleep disorders. Design, Setting, and Patients Inclusion required an Epworth Sleepiness Scale (ESS) score greater than 10 and any subjective nocturnal sleep concern, usually insomnia. An acclimation and screening polysomnogram was performed to exclude subjects with sleep-disordered breathing. The following evening, subjects underwent another polysomnogram, followed by an evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) while practically defined off ("off") PD medications, ESS (primary efficacy point), Pittsburgh Sleep Quality Inventory, and Fatigue Severity Scale. Subjects then started sodium oxybate therapy, which was titrated from 3 to 9 g per night in split doses (at bedtime and 4 hours later) across 6 weeks, and returned for subjective sleep assessments. They then returned at 12 weeks after initiating therapy for a third polysomnogram, an off-medication UPDRS evaluation, and subjective sleep assessments. Data are expressed as mean (SD).. We enrolled 38 subjects. At screening, 8 had sleep apnea (n = 7) or depression (n = 1). Twenty-seven of 30 subjects completed the study. Three dropped out owing to dizziness (n = 3) and concurrent depression (n = 1). The mean dose of sodium oxybate was 7.8 (1.7) g per night. The ESS score improved from 15.6 (4.2) to 9.0 (5.0) (P < .001); the Pittsburgh Sleep Quality Inventory score, from 10.9 (4.0) to 6.6 (3.9) (P < .001); and the Fatigue Severity Scale score, from 42.9 (13.2) to 36.3 (14.3) (P < .001). Mean slow-wave sleep time increased from 41.3 (33.2) to 78.0 (61.2) minutes (P = .005). Changes in off-medication UPDRS scores were not significant, from 28.4 (10.3) to 26.2 (9.6).. Nocturnally administered sodium oxybate improved excessive daytime sleepiness and fatigue in PD.. clinicaltrials.gov Identifier: NCT00641186.

Topics: Adjuvants, Anesthesia; Adult; Aged; Antiparkinson Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Parkinson Disease; Polysomnography; Sleep Apnea Syndromes; Sleep Initiation and Maintenance Disorders; Sleep Stages; Sleep Wake Disorders; Sodium Oxybate; Treatment Outcome

We have recently reported that parkinsonian patients show a significant GH response to gamma-hydroxybutyric acid (GHB), but not to gamma-aminobutyric acid (GABA)-ergic drug administration. In order to establish whether muscarinic cholinergic receptors mediate the GH secretion induced by GHB, normal men and parkinsonian patients were tested with GHB both in the absence and in the presence of the anticholinergic agent, pirenzepine. Both normal controls and parkinsonian patients showed a significant serum GH rise in response to GHB (25 mg/kg body weight p.o.) even though a slightly, but significantly lower response was observed in parkinsonian patients. Pretreatment with pirenzepine (100 mg p.o. 2 h before GHB) completely suppressed the GHB-induced GH release in both normal controls and parkinsonian patients. These data indicate that a cholinergic mechanism mediates the GH response to GHB in normal men. In addition the data indicate that this pathway is preserved in the parkinsonian brain.

Topics: Aged; Area Under Curve; Human Growth Hormone; Humans; Male; Middle Aged; Muscarinic Antagonists; Neurosecretory Systems; Parkinson Disease; Pirenzepine; Receptors, Muscarinic; Sodium Oxybate

The observation that baclofen stimulates growth hormone (GH) secretion in normal men, but not in parkinsonian patients led us to test the GH releasing effect of other gamma-amino-butyric acid (GABA)ergic agents with different mechanisms of action in Parkinson's disease. For this purpose 10 normal men and 10 de novo parkinsonian patients were tested with sodium valproate (800 mg PO), gamma-hydroxybutyric acid (GHB) (25 mg/kg body weight PO) and baclofen (10 mg PO). All drugs induced a significant increment in serum GH levels in the normal controls. On the other hand, GH secretion in parkinsonian patients did not change after baclofen or sodium valproate administration, whereas it showed normal responsiveness to GHB. These data suggest that the mechanism underlying the GH response to GHB is different from that (or those) mediating sodium valproate and/or baclofen action. In addition, the former, but not the latter mechanism appears to be preserved in the parkinsonian brain.

Topics: Aged; Baclofen; GABA Agents; GABA Agonists; gamma-Aminobutyric Acid; Growth Hormone; Humans; Male; Middle Aged; Parkinson Disease; Sodium Oxybate; Valproic Acid

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.

Topics: Calcium; Dopaminergic Neurons; Glutamates; Humans; NADP; Parkinson Disease; Sodium Oxybate; Synucleins

Topics: Aged; Humans; Male; Parkinson Disease; Polysomnography; REM Sleep Behavior Disorder; Sodium Oxybate