Acute Alertness-Promoting Effects of a Novel Histamine Subtype-3 Receptor Inverse Agonist in Healthy Sleep-Deprived Male Volunteers

Abstract

The alertness-promoting effect of MK-0249 (10 or 50 mg), a histamine subtype-3 receptor (HRH3) inverse agonist (IA), was evaluated in the stimulant reference sleep deprivation model (SRSDM) using a double-blind, double-dummy, placebo- and modafinil- (200 mg) controlled, four-period crossover design in 24 healthy young men. The two primary hypotheses were related to sleep latency (first appearance of one epoch of stage 2, 3, or 4 or REM sleep, as detected using polysomnography (PSG)) at 8:00 AM on day 2. Statistically significant increases in sleep latency were observed in association with the use of modafinil 200 mg (9.07 min; P < 0.0001), MK-0249 50 mg (5.17 min; P = 0.008), and MK-0249 10 mg (5.45 min; P = 0.005) at the maintenance of wakefulness test (MWT) at 8:00 AM. Sleep latency was higher when averaged over all MWT time points (P < 0.0001 for modafinil and for both doses of MK-0249). The alertness-promoting effect with the use of MK-0249 in the SRSDM suggests that HRH3 IAs may be effective in disorders involving excessive somnolence.

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

“…The aim of the study was to assess the acute wake promoting effects of MK 0249 using a sleep deprivation model in healthy male volunteers. The primary outcome variable of this study was sleep latency on the MWT, and these data have been reported elsewhere (Iannone et al 2010). Here we report data on the effects of MK-0249 and modafinil on the spectral composition of the EEG during the MWT, sleep structure during recovery sleep as well as effects on the spectral compostion of NREM and REM sleep.…”

“…Here we report data on the effects of MK-0249 and modafinil on the spectral composition of the EEG during the MWT, sleep structure during recovery sleep as well as effects on the spectral compostion of NREM and REM sleep. Details of the protocol can be found in (Iannone et al 2010). …”

“…We previously reported that the novel H3 inverse agonist MK-0249, similar to modafinil, exerts significant wake promoting effects as assessed by the latency to sleep onset during MWTs in a sleep deprivation paradigm (Iannone, et al 2010). In that report we did not present data on the quantitative analysis of the EEG during the sleep deprivation or during the recovery sleep.…”

“…Participants also completed a series of psychometric tests as part of the protocol, the result of which are presented in (Iannone et al 2010). During times when participants were not completing tests they were allowed to move around in the unit and carry out various activities such as watching TV, playing games and reading.…”

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

“…A potential role for H3 IAs is also advocated in obesity and ethanol addiction (7,12). In a study of sleep-deprived healthy male volunteers using the stimulant reference sleep deprivation model, a single 10-mg dose of MK-0249 was associated with alerting effects (13). In essential tremor, however, a recent human trial using MK-0249 did not find significant effects in tremor reduction even at high single dose doses of H3 IA administration (14).…”