Promotion of sleep by targeting the orexin system in rats, dogs and humans
Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, et al.;
Commented by , 28 Feb 2007
Aim of the study
In the last 8 years the discovery of the crucial role played by orexins and their receptors in the control of wakefulness and sleep in both animals and humans has led to an explosion of research in this field. Now an orally available orexin receptor antagonist (ACT-078573) has become available, and this translational report describes its effects on sleep in the first-into-man study, as well as in rats and dogs.
Method
In the human study, groups of 6 subjects were administered single doses of up to 1000 mg ACT-078573, or placebo, or zolpidem 10 mg in the morning and a 25 minute sleep opportunity period was recorded with EEG etc. at 90 minutes and again at 6.5 hours after dosing.
Visual analog ratings of alertness were also recorded and a close watch kept for signs of cataplexy. This is because in human narcolepsy with cataplexy there is orexin deficiency, and cataplectic dogs have orexin receptor mutations, so blocking orexin receptors might possible have induced cataplexy.
The rats were maintained on a 12-h light/12-h dark cycle and implanted with telemetry equipment to record sleep. They were dosed either at the beginning of the active or the beginning of the quiet period. They were also studied during repeated evening doses over 5 days. Dogs were dosed either in the morning or at late evening and monitored by video for signs of sleepiness or cataplexy.
Results
Both humans and animals studied in the normally active period fell asleep more readily and were generally sleepier after dosing with ACT-078573. In humans the effect of 400 mg of the study compound was approximately equivalent to zolpidem 10 mg. In animals this effect was only present during the normal active period, when orexin levels are high.
The duration of effect was about twice as long as zolpidem. There were no serious adverse events, no evidence of cataplexy (although there was no emotional challenge in humans) and no other symptoms except for those associated with increased sleepiness.
In humans and rats both NREM and REM sleep were increased and in dogs there was evidence of increased twitching of head and foot muscles during sleep, a surrogate marker of REM. Sleep-promoting effects were maintained over 5 days repeated dosing in rats.
Dr Wilsons's and Prof Nutt's comments
This is the first human study with an agent affecting the orexin system in humans. ACT-078573 is a dual antagonist, affecting both OR1 and OR2 types. It makes humans, dogs and rats sleepy at a time when they are normally awake. The importance of this is twofold; an oral preparation such as this will allow investigation of the role of endogenous orexins in sleep-wake regulation in humans, and secondly this may be a new avenue in the treatment of sleep disorders.
There is an interesting commentary in the same issue of Nature Medicine by eminent researchers Thomas Scammel and Clifford Saper from Harvard (ref. 1), who point out that as well as its relevance to sleep-wake function, orexin signalling is strongly implicated in the mechanism of reward. They discuss the implications of Brisbane-Roch et al. for future research in addiction.
References
1. Scammell TE, Saper CB. Orexins: looking forward to sleep, back at addiction. Nature Medicine 2007; 13 (2); 126-128