Ramelteon, marketed as
Rozerem by
Takeda Pharmaceuticals North Americais the largest pharmaceutical company in Japan and Asia and a top 15 pharmaceutical company. The company has over 19,000 employees worldwide and achieved $15.7 billion USD in revenue during the 2008 fiscal year...
, is the first in a new class of sleep agents that selectively binds to the
MT1 and MT2 receptorsA melatonin receptor is a G protein-coupled receptor which binds melatonin.Three types of melatonin receptor have been cloned. The MT1 and MT2 receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 has been identified in amphibia and...
in the
suprachiasmatic nucleusThe suprachiasmatic nucleus or nuclei, abbreviated SCN, is a tiny region on the brain's midline, situated directly above the optic chiasm. It is responsible for controlling circadian rhythms...
(SCN), instead of binding to GABA
A receptors, such as with drugs like
zolpidemZolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
,
eszopicloneEszopiclone, marketed by Sepracor under the brand-name Lunesta, is a nonbenzodiazepine hypnotic used as a treatment for insomnia. Eszopiclone is the active dextrorotatory stereoisomer of zopiclone, and belongs to the class of drugs known as cyclopyrrolones.Eszopiclone is a short acting...
, and
zaleplonZaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...
. Ramelteon is approved by the U.S. Food and Drug Administration (FDA) for long-term use.
Ramelteon does not show any appreciable binding to GABA
A receptors, which are associated with
anxiolyticAn anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, myorelaxant, and
amnesicAmnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
effects.
Uses
ROZEREM (ramelteon), FDA Approved 07.04.05, can be used for
insomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, particularly delayed sleep onset. Ramelteon has not been shown to produce dependence and has shown no potential for abuse, and the withdrawal and rebound insomnia that is typical with
GABAGabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
modulators is not present in ramelteon. Some clinicians also use ramelteon for the treatment of Delayed sleep phase disorder.
Mechanism of action
Ramelteon is a melatonin receptor
agonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
with both high affinity for
melatonin MT1 and MT2 receptorsA melatonin receptor is a G protein-coupled receptor which binds melatonin.Three types of melatonin receptor have been cloned. The MT1 and MT2 receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 has been identified in amphibia and...
and
selectivityFunctional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
over the MT
3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT
1 or MT
2 receptors, and high selectivity for human MT
1 and MT
2 receptors compared to the MT
3 receptor.
The activity of ramelteon at the MT
1 and MT
2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind
neuropeptideNeuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
s,
cytokineCytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s,
serotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
,
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, noradrenaline,
acetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, and
opiateIn medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
s. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel.
The significance of ramelteon's lack of affinity for the MT
3 receptor is not clear, despite the manufacturer's emphasis of this fact in commercial advertisements. The MT
3 receptor appears almost exclusively in the gut and might not have any relationship to sleep or wakefulness.
The major
metaboliteMetabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT
1 and MT
2 receptors, respectively, and is 17 – 25-fold less potent than ramelteon in
in vitro functional assays. Although the potency of M-II at MT
1 and MT
2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20 – 100 fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.
All other known metabolites of ramelteon are inactive.
No published studies have indicated whether ramelteon, in humans, is more or less safe or effective than the hormone
melatoninMelatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
which it mimics; melatonin is much less expensive and is widely available over-the-counter in the US and Canada. The biological action of melatonin is similar to that of ramelteon. Ramelteon has been directly compared to melatonin in cats, and Ramelteon had a significant (3x) longer effect and had a more profound effect on the EEG of the sleeping cats.
Clinical efficacy
In a double-blind multicenter trial, ramelteon did reduce the time to fall asleep by approximately 15-20 minutes, at 8 mg and 16 mg doses after four weeks compared to placebo (approx. 29-32 versus 48 minutes) Total sleep time improved about 40 minutes, however, this was identical to improvement with placebo at the end of trial. Subjective reported sleep time was greater in ramelteon treated persons. The main thing to note is ramelteon compared to placebo had a much faster onset of effects, one or two weeks, but the effects were roughly equivalent to placebo at four weeks.
Adverse effects
Ramelteon caused
hyperprolactinaemiaHyperprolactinaemia or hyperprolactinemia is the presence of abnormally-high levels of prolactin in the blood. Normal levels are less than 500 mIU/L for women, and less than 450 mIU/L for men....
two to three times more often than placebo in clinical trials. Studies of rats and mice showed a dose-dependent increase in cancer. The long-term safety in humans is unknown.
Ramelteon was teratogenic in rats.
Drug interactions
Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects:
omeprazoleOmeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
,
theophyllineTheophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
,
dextromethorphanDextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
, and
midazolamMidazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
,
digoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
and
warfarinWarfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
. There were no clinically meaningful effects when ramelteon was coadministered with any of these drugs.
A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI Prozac (fluoxetine) were coadministered. Ramelteon and
fluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
should not be coadministered.
Ramelteon should be administered with caution in patients taking other
CYP1A2Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
inhibitors, strong
CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
inhibitors such as
ketoconazoleKetoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, and strong
CYP2C9Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
inhibitors such as
fluconazoleFluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
.
Efficacy may be reduced when ramelteon is used in combination with potent
CYPThe cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
enzyme inducers such as rifampin, since ramelteon concentrations may be decreased.
Advertising campaign
Rozerem has become known for the surreal humor of its television advertisements, particularly one involving an
insomniacInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
chatting with
Abraham LincolnAbraham Lincoln was the 16th President of the United States, serving from March 1861 until his assassination in April 1865. He successfully led his country through a great constitutional, military and moral crisis – the American Civil War – preserving the Union, while ending slavery, and...
and a talking
beaverThe beaver is a primarily nocturnal, large, semi-aquatic rodent. Castor includes two extant species, North American Beaver and Eurasian Beaver . Beavers are known for building dams, canals, and lodges . They are the second-largest rodent in the world...
over a
chessChess is a two-player board game played on a chessboard, a square-checkered board with 64 squares arranged in an eight-by-eight grid. It is one of the world's most popular games, played by millions of people worldwide at home, in clubs, online, by correspondence, and in tournaments.Each player...
board, while a
hard-hat diverA standard diving dress consists of a metallic diving helmet, an airline or hose from a surface supplied diving air pump, a canvas diving suit, diving knife and boots...
stands silently in the background. As of October, 2007, the most recent spot was framed as a late-night talk show, with the beaver as host, Lincoln as sidekick, a Rozerem expert as guest, and the diver as bandleader.
Chemistry
Sources and external links