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One sleep disorder throws light on another

January 28, 2007 By Heidi Ledford This article courtesy of Nature News.

Treatment based on narcolepsy could promote sleep in insomniacs.

By learning from patients who nod off unexpectedly during the day, researchers have pinpointed a chemical that could help people who can't sleep at night.

One out of every 10 people in the United States suffers from chronic insomnia, making for a big sleeping-pill market. The most popular pills work by strengthening the effects of a brain chemical that slows the nervous system and promotes relaxation. But these drugs can also carry unpleasant side effects, including memory loss and grogginess the next day. The race for a better sleeping pill is still on.

Now, a new approach targets brain hormones called orexins. Orexins are known to be linked to sleepiness; patients with a sleeping disorder called narcolepsy have low levels of these hormones and are chronically sleepy during the day, sometimes falling asleep on the job or while driving.

The new chemical, known as ACT-078573, blocks the action of orexins. When given to dogs, rats and humans, it decreased alertness in all three species, while shortening the time it took for them to fall asleep. François Jenck, of the Swiss biotech company Actelion Pharmaceuticals in Allschwil, and his colleagues report the findings in the journal Nature Medicine1.

More time needed

Orexins aren't an obvious target for developing new sleeping pills. Narcoleptics suffer not only from sleepiness, but also from sudden loss of muscle tone that, in extreme cases, can cause them to collapse and remain frozen - fully conscious - for minutes at a time. Laughter often triggers a collapse in human narcoleptics, whereas narcoleptic dogs can crumple from the thrill of dinnertime or being let loose to play in the yard. "They get excited and run out the door and just go 'thump'," says Jerome Siegel, a sleep researcher at the University of California, Los Angeles.

But the new drug seems to bring none of these side effects, says Jenck. People taking the drug reported no loss of muscle tone or lack of coordination or hallucinations, another common problem for narcoleptics while falling asleep or awakening.

Other experts are quick to caution that the tests are preliminary, and that the drug must be tested over much longer periods of time to be sure it is safe and effective.

Seiji Nishino, a sleep researcher at Stanford University in California, notes that the data come from a single drug dose given to 42 healthy males with no history of sleep disorders. Most insomniacs, he says, suffer chronically abnormal sleep and would need long-term treatment. And although the compound made patients sleepy during the day when orexin levels are high, it remains to be seen whether it will have the same effect at night, when orexin levels are already naturally low. Jenck says that Actelion is currently testing the drug over the long-term in insomniacs.

Nishino also points out that patients diagnosed with narcolepsy often don't experience abrupt loss in muscle tone until six months to a year after they began to experience daytime drowsiness. That means it's possible that the effects on muscle tone won't show up until the brain has been starved of orexins for some period of time, he says.

Meanwhile, orexins have also been implicated in regulating appetite and feelings of reward. So the new drug could potentially have additional side effects or applications for weight maintenance and drug addiction. "If we consider these other functions of orexin," says Nishino, "there are likely to be other important uses for the compound."

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  1. Jenck F., et al. Nature Med., doi:10.1038/nm1544 (2007).


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