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 (10or 50mg), 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- (200mg) 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 8:00AM on day 2. Statistically significant increases in sleep latency were observed in association with the use of modafinil 200mg (9.07min; P<0.0001), MK-0249 50mg (5.17min; P = 0.008), and MK-0249 10mg (5.45min; P = 0.005) at the maintenance of wakefulness test (MWT) at 8:00AM. 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. © 2010 American Society for clinical Pharmacology and Therapeutics.