Sodium oxybate increases prolactin secretion in narcolepsy patients and healthy controls

Contains fulltext : 98354.pdf (publisher's version ) (Open Access)OBJECTIVE: Hypocretin deficiency causes narcolepsy and may affect neuroendocrine systems, including TSH, ACTH and LH secretion. Symptoms can be treated effectively with sodium oxybate (SXB) in many patients. This study was performed to compare prolactin (PRL) secretion in patients and matched controls and establish the effect of SXB administration on PRL and sleep in both the groups. DESIGN: Open label intervention. Blood was sampled before and after 5 days of SXB treatment. The study was performed at the Leiden University Medical Centre, Leiden, The Netherlands. METHODS: Subjects were admitted to the clinical research centre on both occasions. PATIENTS OR PARTICIPANTS: Eight male hypocretin-deficient narcolepsy with cataplexy patients and eight controls matched for sex, age, body mass index, waist-to-hip ratio and fat percentage were enrolled. INTERVENTIONS: SXB two times 3 g per night for five consecutive nights. RESULTS: Patients and controls underwent 24 h blood sampling at 10 min intervals for measurement of PRL concentrations. The PRL concentration time series was analysed with a new deconvolution programme, approximate entropy (ApEn) and Cosinor analysis. Sleep was polygraphically recorded. Basal and pulsatile PRL secretion, as well as pulse regularity and frequency, ApEn and diurnal parameters were similar in patients and controls. SXB treatment caused similar nocturnal increase in PRL secretion, advance of the acrophase and decrease in ApEn in patients and controls. Slow wave sleep was increased to a similar extent in patients and controls. CONCLUSION: This detailed study did not demonstrate altered PRL secretion in hypocretin-deficient narcolepsy patients during the basal state or during SXB administration. Therefore, hypocretin signalling is unlikely to be a regulator of the lactotrophic system

Glucose and fat metabolism in narcolepsy and the effect of sodium oxybate: a hyperinsulinemic-euglycemic clamp study

INTRODUCTION: Narcolepsy is associated with obesity though it is uncertain whether this is caused by changes in glucose and fat metabolism. Therefore, we performed a detailed analysis of systemic energy homeostasis in narcolepsy patients, and additionally, investigated whether it was affected by three months of sodium oxybate (SXB) treatment. METHODS: Nine hypocretin deficient patients with narcolepsy-cataplexy, and nine healthy sex, age, and BMI matched controls were enrolled. A hyperinsulinemic-euglycemic clamp combined with stable isotopes ([6,6-(2)H2]-glucose and [(2)H5]- glycerol) was performed at baseline. In seven patients a second study was performed after three months of SXB treatment. RESULTS: Glucose disposal rate (GDR) per unit serum insulin was significantly higher in narcolepsy patients compared to matched controls (1.6 +/- 0.2 vs. 1.1 +/- 0.3 mumol/kgFFM/min/mUxL; P = 0.024), whereas beta-cell function was similar (P = 0.50). Basal steady state glycerol appearance rate tended to be lower in narcolepsy patients (5.2 +/- 0.4 vs. 7.5 +/- 1.3 mumol/kgFM/min; P = 0.058), suggesting a lower rate of lipolysis. SXB treatment induced a trend in reduction of the GDR (1.4 +/- 0.1 vs. 1.1 +/- 0.2 mumol/kgFFM/min/mUxL; P = 0.063) and a reduction in endogenous glucose production (0.24 +/- 0.03 vs. 0.16 +/- 0.03 mumol/kgFFM/min/mUxL: P = 0.028) per unit serum insulin. After SXB treatment lipolysis increased (4.9 +/- 0.4 vs. 6.5 +/- 0.6 mumol/kgFM/min; P = 0.018), and body weight decreased in narcolepsy patients (99.2 +/- 6.0 vs. 94.0 +/- 5.4 kg; P = 0.044). CONCLUSION: We show that narcolepsy patients are more insulin sensitive and may have a lower rate of lipolysis than matched controls. SXB stimulated lipolysis in narcolepsy patients, possibly accounting for the weight loss after treatment. While sodium oxybate tended to decrease systemic insulin sensitivity, it increased hepatic insulin sensitivity, suggesting tissue-specific effects. CITATION: Donjacour CE; Aziz NA; Overeem S; Kalsbeek A; Pijl H; Lammers GJ. Glucose and fat metabolism in narcolepsy and the effect of sodium oxybate: a hyperinsulinemic-euglycemic clamp study. SLEEP 2014;37(4):795-801

Efficiency of autoregulatory homeostatic responses to imposed caloric excess in lean men (vol 294, pg E808, 2008)

Diabetes mellitus: pathophysiological changes and therap

The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency

Item does not contain fulltextBACKGROUND: Narcolepsy is often not recognized or accurately diagnosed. This may be due to the fact that cataplexy, a core symptom which is virtually 100% specific, can-in practice-only be diagnosed based on the patient's history. However, the current definition of cataplexy is not very precise and the common distinction between "typical" and "atypical" cataplexy is not well codified. METHODS: We aimed to provide a detailed description of the phenotypic variability of cataplexy. We included 109 patients with a definite history of cataplexy and a proven hypocretin-1 deficiency. The questionnaire contained 37 items to broadly cover the clinical aspects of cataplexy, including triggers, pattern and duration of muscle weakness, associated aspects such as sensory phenomena, and limitations in daily life due to cataplexy. RESULTS: "Laughing" only listed in place 11th of most frequent triggers. "Laughing excitedly" was much more potent, showing that a certain intensity of the emotion is important for a "cataplectogenic" effect. Anger was the highest ranking "non-humorous" trigger, followed by "unexpectedly meeting someone well known." About 60% of patients also had spontaneous cataplectic attacks. Forty-five percent of patients experienced both partial and complete attacks and 30% only partial cataplexy. Fifteen percent of complete attacks were reported to last longer than 2 min. An abrupt return of muscle function was an important feature. The jaw and the face were most often involved in partial attacks, even more than the knee or the leg. CONCLUSIONS: Cataplexy presents with a large phenotypical diversity, so the current "typical" versus "atypical" distinction may be difficult to hold. We propose that grading cataplexy with different levels of diagnostic confidence may be more useful

The effects of sodium oxybate on core body and skin temperature regulation in narcolepsy

Contains fulltext : 154173.pdf (publisher's version ) (Closed access)Patients suffering from narcolepsy type 1 show altered skin temperatures, resembling the profile that is related to sleep onset in healthy controls. The aim of the present study is to investigate the effects of sodium oxybate, a widely used drug to treat narcolepsy, on the 24-h profiles of temperature and sleep-wakefulness in patients with narcolepsy and controls. Eight hypocretin-deficient male narcolepsy type 1 patients and eight healthy matched controls underwent temperature measurement of core body and proximal and distal skin twice, and the sleep-wake state for 24 h. After the baseline assessment, 2 x 3 g of sodium oxybate was administered for 5 nights, immediately followed by the second assessment. At baseline, daytime core body temperature and proximal skin temperature were significantly lower in patients with narcolepsy (core: 36.8 +/- 0.05 degrees C versus 37.0 +/- 0.05 degrees C, F = 8.31, P = 0.01; proximal: 33.4 +/- 0.26 degrees C versus 34.3 +/- 0.26 degrees C, F = 5.66, P = 0.03). In patients, sodium oxybate administration increased proximal skin temperature during the day (F = 6.46, P = 0.04) to a level similar as in controls, but did not affect core body temperature, distal temperature or distal-proximal temperature gradient. Sodium oxybate administration normalised the predictive value of distal skin temperature and distal-proximal temperature gradient for the onset of daytime naps (P < 0.01). In conclusion, sodium oxybate administration resulted in a partial normalisation of the skin temperature profile, by increasing daytime proximal skin temperature, and by strengthening the known relationship between skin temperature and daytime sleep propensity. These changes seem to be related to the clinical improvement induced by sodium oxybate treatment. A causal relationship is not proven

Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study

Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness, irresistible sleep episodes, and sudden loss of muscle tone (cataplexy) mostly triggered by emotions. Narcolepsy with cataplexy is a disabling lifelong disorder frequently arising during childhood. Pediatric narcolepsy often results in severe learning and social impairment. Improving awareness about this condition increases early diagnosis and may allow patients to rapidly access adequate treatments, including pharmacotherapy and/or non-medication-based approaches. Even though children currently undergo pharmacotherapy, data about safety and efficacy in the pediatric population are scarce. Lacking international guidelines as well as drugs registered for childhood narcolepsy with cataplexy, physicians have no other alternative but to prescribe in an off-label manner medications identical to those recommended for adults. We retrospectively evaluated 27 children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy, who had been treated with off-label sodium oxybate and had been followed in a clinical setting. Throughout a semi-structured interview, we documented the good efficacy and tolerability of sodium oxybate in the majority of the patients. This study constitutes a preliminary step towards a further randomized controlled trial in childhood narcolepsy with cataplexy