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Sleep
Efficacy and Safety of Circadin
®
in the Treatment of Primary Insomnia
a report by
Nava Zisapel, PhD
1
and Patrick Lemoine, MD, PhD
2
1. Department of Neurobiology, Faculty of Life Sciences, Tel Aviv University, and Neurim Pharmaceuticals Ltd, Tel Aviv;
2. International Medical Director, CLINEA-ORPEA
Circadin
®
(Neurim Pharmaceuticals) is a prolonged-release formulation of 2mg for a drug that improves quality of sleep. Thus, treatment focus has shifted to
melatonin (PR-melatonin 2mg) that, when taken before bedtime, mimics the re-establishing restorative sleep, improving daytime functioning and quality of
physiological pattern of melatonin excretion during the night. It was approved life, and avoiding withdrawal symptoms.
26–28
by the European Medicines Agency (EMEA) in June 2007 for the short-term
treatment of primary insomnia characterized by poor quality of sleep in Melatonin—A Physiological Sleep Regulator
patients over 55 years of age. PR-melatonin 2mg is a first-class medicine that Melatonin (N-acetyl-5-methoxytryptamine) is produced by the pineal gland in
goes beyond the facilitation of sleep onset of other widely used drugs for a process that is regulated by the internal biological clock, which is localized
insomnia. This is due to its ability to improve sleep quality, next-day alertness, in the suprachiasmatic nuclei (SCN) of the hypothalamus and inhibited by light
and quality of life. No significant adverse events were found with PR-melatonin perceived by the retina.
29
Normally, endogenous melatonin levels rise soon
2mg compared with placebo. It can be used concomitantly with most after the onset of darkness, peak in the middle of the night, and gradually
medications, but potentiates the hypnotic effects of gamma-aminobutyric acid decline toward the morning.
30
Melatonin serves as a physiological signal of
(GABA
A
) receptor modulators. In contrast to traditional sedative hypnotics, it darkness to re-set the biological clock in order to match the environmental
has shown no evidence of impairing cognitive or psychomotor skills, or of day–night cycle and regulate the sleep–wake and other circadian rhythms
dependence or abuse potential. (e.g. temperature, blood pressure, and hormones).
31–33
Melatonin undergoes
first-pass hepatic metabolism (half-life in human serum is approximately
Insomnia—Symptoms, Daytime Disturbances, and 40 minutes)
34
and over 80% is excreted exclusively in the urine as
Treatment Options 6-sulfatoxymelatonin (6-SMT).
35
Melatonin is thought to act via its own
Insomnia is the common complaint of difficulty initiating or maintaining sleep receptors (MT1, MT2), which are members of the G-protein-linked receptor
and/or experiencing poor quality of sleep (also termed non-restorative sleep, a family.
36
The presence of MT1 and MT2 receptors in the SCN, hippocampus,
subjective complaint about tiredness on waking and throughout the day, and other brain areas, and melatonin’s physiological activities in these areas,
feeling rested and restored on waking, and the number of awakenings implicates these receptors in the regulation of sleep and circadian rhythms
experienced during the night) over at least one month and with negative and, perhaps, memory consolidation.
37–42
effects on subsequent daytime functioning.
1–3
Patients may suffer immensely
from a poor quality of sleep while their sleep quantity is within the normal Circadin—A Prolonged-release Melatonin Formulation
limits.
1,2
Insomnia is a very common disorder, and its prevalence increases with The production of melatonin decreases with age.
43–45
Lower production of
age
4–7
and is 1.5 times higher in women than in men.
8,9
The disorder may be melatonin was found in patients above 55 years of age who suffered from
primary, namely not attributable to any known physical or mental condition
or environmental cause, or secondary, resulting from an existing physical or
Nava Zisapel, PhD, is a Professor at Tel Aviv University
mental condition. The prevalence of poor sleep quality increases with age.
10–12
specializing in neurobiology and biological clocks. She is the
Insomnia also has negative consequences on health-related quality of life.
13–17
incumbent of the Michael Gluck Chair in neuropharmacology
More so than poor sleep quantity, poor sleep quality corresponds negatively to
and amyotrophic lateral sclerosis research. In 1991 she founded
Neurim Pharmaceuticals in Tel Aviv, and she serves as Chief
physical and mental measures of health, wellbeing, activities of daily living,
Scientific Officer of the company. With her colleagues she has
driving skills, memory, productivity, and satisfaction with life.
10,11,18–23
written over 170 papers in peer-reviewed journals. Dr Zisapel
holds a BSc in chemistry, an MSc in biochemistry, and a PhD in
biochemistry from Tel Aviv University.
The management of insomnia involves non-pharmacological and
pharmacological approaches, and traditionally focuses on alleviating difficulties
E:
navazis@post.tau.ac.il
in initiating or maintaining sleep. The most commonly prescribed drugs for
Patrick Lemoine, MD, PhD, is International Medical Director of
insomnia are benzodiazepines (e.g. temazepam) and non-benzodiazepine (e.g. CLINEA-ORPEA, a group that includes 20 psychiatric institutions in
zopiclone, zolpidem) hypnotics, which potentiate the central nervous system
France, Switzerland, and Italy. Previously, he was Medical Director
of Unité Clinique de Psychiatrie Biologique (UCPB) at Vinatier
(CNS)-suppressant activity of brain GABA
A
receptors.
24
None of these improve
Hospital in Lyon, and was a Research Fellow at Stanford University
subsequent daytime functioning and they are all associated with a higher risk and a Research Associate at Montreal (Philippe Pinel Research
for driving accidents, falls and fractures, overdose, and cognitive impairment,
Center) between 1996 and 1999. Dr Lemoine has published 20
books and over 300 papers.
along with the potential for abuse and dependence;
25
therefore, their use is
discouraged, particularly in elderly patients.
26
An unmet medical need remains
© TOUCH BRIEFINGS 2008
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