In the issue of Science Translational Medicine published on April 3, 2013, Uslaner et al. of the American pharmaceutical company Merck report on a new class of hypnotics, which are characterized by a completely new mechanism of action (Uslaner et al., Sci Transl Med 2013). It is called DORA (dual orexin receptor antagonists). In an editorial in the issue of Science published on April 5, 2013, Emmanuel Mignot of Stanford University in California asks the question whether a DORA could be “The Perfect Hypnotic?” (Mignot, Science 2013).
Hypnotics are today essentially benzodiazepines and the so-called Z-drugs, with the latter increasingly displacing the former at least in the hypnotic indication, because they have a more favorable pharmacokinetic profile and the risk for development of tolerance and abuse is somewhat lower. It is these risks that limit the use of benzodiazepines and Z-drugs. In many countries, their prescription is subject to time limitations (in Germany four weeks, in the United States four months) and other surveillance measures. Since many patients and their doctors are hesitant to take or prescribe, respectively, these medicines, antihistamines or antihistaminic acting antidepressants are prescribed as alternatives. For this indication, they were never tested or approved. 10-15% of the U.S. population suffers from chronic insomnia. In many industrialized countries, this is likely to be similar. Since these are not always and not always sufficiently influenced through behavioral interventions, there is a significant need for hypnotics that do not act via the GABA/benzodiazepine receptor complex.
Orexins (= hypocretines) are neurotransmitters, which play a key role in the maintenance of wakefulness in the CNS of humans. They are produced by only about 70,000 neurons in the hypothalamus, however, extensive projections excite other important alertness sustaining brain regions. The reduction in the activity of these centers through blockade of orexin receptors is therefore considered a more physiological approach to induce sleep compared to the global inhibition of brain activity by increasing GABAergic activity. Orexins were discovered in 1998. There are two types, A and B, resulting from the same pre-propeptide. A little later, in 2000, it was discovered that narcolepsy appears to be due in most cases to a deficient neurotransmission via the orexin system.
Uslaner et al. now compared their experimental substance DORA-22 with the benzodiazepine diazepam and the Z-drugs zolpidem and eszopiclone regarding their hypnotic and cognitive effects in rats and rhesus monkeys. The researchers determined for each compound the minimum hypnotic dose and the minimum dose that caused impairment in cognitive tests. This results in a certain therapeutic margin for each drug. In both species DORA-22 had a greater therapeutic index than the three reference substances. This means that the new class, at least in terms of their (unwanted) effects on cognitive function, promises to be better tolerated than the available GABAergic hypnotics.
Merck submitted the DORA suvorexant for approval to the U.S. FDA. Several studies on the efficacy and tolerability of the substance were carried out, one was published in 2012 in the journal Neurology (Herring et al., 2012). In this double-blind, placebo-controlled study of four different doses of suvorexant (10, 20, 40 and 80 mg) were tested against placebo for four weeks. Suvorexant was dose-dependently superior to placebo in improving sleep efficiency. Also, the induction and maintenance of sleep were dose-dependently favorably affected. Data on the possible development of tolerance to the effects of suvorexant after long-term use have not yet been published. This will be crucial for the acceptance of this new drug class.
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