Biomedical Engineering Reference
In-Depth Information
O
MeO
NH
NH
O
O
NH
Melatonin
Ramelteon
FIGURE 20.11
Structures of melatonin and the melatonergic agonist ramelteon.
bring a person with a disrupted sleep pattern in synchrony with their normal circadian rhythm.
Several studies have provided contradictory results for melatonin; a situation that has led to a
discussion about the value of melatonin as a drug. Data with a modii ed release formulation of
melatonin has consistently demonstrated that in patients with a dysfunctional melatonin system
(e.g., elderly), subjective sleep parameters and subjective daytime quality of life were signii cantly
enhanced after 4 weeks of treatment. This formulation of melatonin was approved for primary
insomnia in elderly and may rel ect a change in the attitude of the European authorities, such that
subjective parameters are sufi cient for obtaining regulatory approval. In addition to melatonin,
one melatonergic agonist is currently approved for insomnia in the U.S. Ramelteon (Figure 20.11)
has been demonstrated to robustly induce sleep (using polysomnography-EEG measurements) in
primary insomniacs. However, the effects in terms of minutes faster asleep are smaller than those
observed for BzRAs. This does not necessarily predict a weaker effect on daytime performance.
A correlation between reduction in time to sleep and subjective (or objective) daytime performance
has never been established. The really exciting aspect of these compounds is therefore not whether
they may induce or maintain sleep, but whether they will have positive consequences for the qual-
ity of life during the day.
20.4 CONCLUDING REMARKS
The development of hypnotics has for years been limited by our lack of insight into the mechanisms
underlying sleep and how these translate into daytime function. With the ongoing integration of
electrophysiology, molecular biology, imaging techniques, and cognitive research, focus in insom-
nia is moving from sleep induction and maintenance to effects of sleep on cognition and other types
of daytime performance. The acceptance of insomnia as a chronic disease of its own and not as a
symptom of other diseases stresses the need for novel types of hypnotic drugs. The coming years
may therefore open up for hypnotic compounds focusing entirely on cognitive or psychiatric conse-
quences of insomnia. The desired receptor proi le of such compounds still remains to be established
and this together with the medicinal chemistry challenges will be a challenge in the coming decade.
FURTHER READINGS
Akerstedt, T., Billiard, M., Bonnet, M., Ficca, G., Garma, L., Mariotti, M., Salzarulo, P., and Schultz, H. 2002.
Awakening from sleep.
Sleep Med. Rev
. 6: 267-286.
Curry, D.T., Eisenstein, R.D., and Walsh, J.K. 2006. Pharmacologic management of insomnia: Past, present,
and future.
Psychiatr. Clin. North Am
. 29: 871-893.
Ebert, B., Wafford, K.A., and Deacon, S. 2006. Treating insomnia: Current and investigational pharmacological
approaches.
Pharmacol. Ther
. 112: 612-629
Kryger, M., Roth T., and Dement W.C., eds.
Principles and Practice of Sleep Medicine
. Philadelphia: W.B.
Saunders, 2005.
NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in
adults. 2005.
NIH Consens. State Sci. Statements
22: 1-30.
Nofzinger, E.A. 2004. What can neuroimaging i ndings tell us about sleep disorders?
Sleep Med
. 5 (Suppl 1):
S16-S22.
