Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

Abstract

Rationale: Histamine and dopamine contribute to the maintenance of wakefulness.Objective: Exploratory analysis of the effects of 10 and 50 mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200 mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep. Methods: 25 healthy men were recruited to a double-blind placebocontrolled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at 2 hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness. Results: After placebo, sleep deprivation was associated with enhancements in delta, theta and reductions in alpha and beta activity.Following dosing at 02:00, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00 h, latency to sleep onset, and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1 % was increased and total sleep time, SWS % and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249 and the 50 mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep.After modafinil, no changes were observed for power spectra during sleep. Conclusion: both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.

11C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

“…1) and have been used in several clinical studies (13,14,19). Both compounds have a nanomolar affinity for H3 receptors and are highly specific for H3 receptors (inhibition constant is .10 mM for H1, H2, and H4, and no other off-target activities below 1 mM).…”

“…The aim of the current study was to evaluate the biodistribution, dosimetry, and quantification of 11 C-MK-8278 in humans and to determine its utility in clinical occupancy studies of 2 novel histamine H3 IAs, MK-0249 (13,14,19) and MK-3134 (20). Open-label, 2-period, multipanel studies were done to investigate occupancies of single oral doses at the time of approximately maximum occupancy (approximate plasma T max ) in the target range of 50%-90% brain H3 RO.…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Narcolepsy is characterized by excessive diurnal sleepiness and can occur alone or as part of other neurologic disorders (e.g., Parkinson's disease). On the basis of the wake-inducing properties of H 3 receptor blockade, pitolisant (45) was developed, together with an apparent ideal pharmacokinetic profile, where a once-aday dose maintains attention over the day, but, importantly, allows individuals to sleep at night (Iannone et al, 2010;James et al, 2011;Schwartz, 2011). Preclinical studies have also suggested the lack of drug abuse liability Histamine Receptors for pitolisant in rodent and primate models, in contrast to modafinil (Uguen et al, 2013).…”

Modafinil Effects on Middle-Frequency Oscillatory Power During Rule Selection in Schizophrenia

“…response to modafinil (Nagels et al, 2007); and after sleep deprivation in healthy subjects, modafinil partly normalized both the increased delta and theta activity, and the reduced alpha and beta activity, that were each observed on placebo (James et al, 2011).…”