If you discover a brain chemical which, when missing or malfunctioning (due to a mutation in its receptor) abruptly puts people and animals to sleep when they don’t want to – a condition called narcolepsy – then you can work on creating a drug that acts in the opposite way and induces sleep when you want to.
Apparently, that is what a Swiss team just did (Nature news report here and Nature blog commentary here). The drug, still without a sexy name, is known by its “code-name” ACT-078573.
The target of the drug is the orexin system. Orexins (also known as hypocretins – the discovery was simultaneous in two laboratories several years ago and both terms are in equal use in the literature – you may remember one of the studies as it received some media coverage because it tested narcoleptic Doberman pinchers) are two closely related neuropeptides (orexin 1 and orexin 2). They are produced by cleavage of a single precursor protein. They are strongly conserved through the vertebrate evolution. They are produced in a small cluster of nerve cells, but those cells make projections widely across the brain.
The major function of orexins is to integrate circadian, sleep and metabolic information to determine if the animal should be awake or asleep. The connection to metabolism is also responsible for a secondary role of orexins in the control of appetite.
In narcoleptic people (or dogs), the levels of orexin are very low, or the orexin receptor is not functioning. In other words, the funciton of orexins is to promote wakefulness. ACT-078573 is an orexin antagonist – it blocks effects of orexin, thus promoting sleepiness.
It is too early to talk to your physician about this drug yet. This was just a first preliminary study. The drug was given only once, so we do not know possible effects of prolonged use. It was given to 42 healthy males with no history of sleep disorders, thus we do not know how it would effect women, children or people WITH sleep disorders – exactly those who would potentially benefit from this drug.
Just because a single use did not provoke other symptoms of narcolepsy – loss of muscle tone, loss of coordination and hallucinations – does not mean that long-term use of the drug would not result in such side-effects (after all, even the early narcoleptic events in affected people do not usually have such side-effects – they develop over time).
Another consideration is timing. In the study, the drug was given during the day when the orexin levels are naturally high (remember – orexin promotes wakefulness). We do not know what effect, if any, the orexin antagonist would have at night when orexin levels are naturally low. After all, as with all drugs targeting the circadian system, the effect is highly dependent on timing.
Another concern is with a possible side-effects of the drug on the appetite. Though this may be turned into a positive for the drug if it can be shown to be useful in control of appetite. Nothing sells better than sleep pills except the diet pills, after all!
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