By Sirinoot Jantharangkul

Ramelteon (RozeremTM ) :melatonin receptor agonist

approved for insomnia

Ramelteon (RozeremTM ) :melatonin receptor agonist

approved for insomnia

Stages of sleep

Non-REM (Non-rapid eye movement)Stage 1: Initiates sleep ,15-30minStage 2: 50%of total sleep timeStage 3/4:15-20%of total sleep time

deep sleep REM (Rapid eye movement)

Dreming occurs

Sleep cycle

90min/cycle (4-5 cycles/night)

Normal sleep

Insomnia

InsomniaInsomnia: characterizes by one or

more of the following: Difficulty falling asleep

Waking up frequently during the night

with difficulty returning to sleep

Waking up too early in the morning

Unrefreshing sleep

Types of insomnia

Transient / Intermittent Insomnia Acute stress or illness Jet lag

Chronic Insomnia Primary or psychophysiological Secondary, refratory to treatment

of medical/ psychiatic disorder

Treatment

Non-pharmacologic therapySleep hygiene information

Stimulus control instructions

Chronotherapy

Treat underlying diseases or causes

Sedative-Hypnotics

Sedative-Hypnotics

Barbiturates

Benzodiazepines (BZDs)

Nonbenzodiazepine drugs

e.g zolpidem,zaleplon,eszopiclone

Characteristics of the ideal sleep agent

No physicaldependence

No tolerance

No effect on memory

Induction ofPhysiologicalSleep pattern

Rapidabsorption

Rapid sleepinduction

No residualsedation

Optimal half-lift

No reboundInsomnia orwithdrawal

No interactionWith alcohol

Ideal Sleep Agent

GABAA agonists

Ideal Sleep Agent

Rapidabsorption

No residualsedation

No reboundInsomnia orwithdrawal

Optimal half-lift

Rapid sleepinductionNo interaction

With alcohol

No physicaldependence

No tolerance

No effect on memory

Induction ofPhysiologicalSleep pattern

The Suprachiasmatic Nucleus (SCN)

SCN

Role of the SCN in the Sleep-Wake cycle

During the day, the SCN emitsan alerting signal that helps maintain Wakefulness.

At night, the alerting signalis attenuated, facilitating the onset of sleep.

Circadian control of melatonin production

SCNMEL

the activity of the SCN increases during the daymelatonin production is very low

SCN activity descends in the late daymelatonin production begins and reaches a peak very rapidly

DAY NIGHT

Melatonin

Melatonin is a hormone

(N-acetyl-5 methoxytryptamine)

Produced by the pineal gland

Regulate sleep-wake cycles

MT1MT2

MT2MT2

MT2

• Localized in hypothalamic suprachiasmatic nucleus and neural retina

•Diffuse expression in brain, liver,heart,kidneys

MT1 and MT2 receptors

Circadian control of melatonin production

MT1receptor

SCN

Melatonin

MT1 Agonists

Promote sleep via MT1Receptor in SCN regulating

Sleep/wake cycle

Physiological Sleep

MT1

Sleep promotion

melatonin receptor agonist

Ramelteon (RozeremTM )

:melatonin receptor agonist

RamelteonGeneric name: Ramelteon (ram el tee on)

Brand name: Rozerem

Company: Takeda Pharmaceuticals

North AmericaFDA Approval: 22 July, 2005

Treatment for: Insomnia

Molecular weight : 259.34 Freely soluble in organic solvents and

very slightly soluble in water

RamelteonRamelteon

Mechanism of action

melatonin receptor agonist with high affinity for melatonin (MT1) receptor

15time more potent than melatonin at MT1receptor

the MT1 receptor is believed to contribute to its sleep-promoting properties

the maintenance of the circadian rhythm underlying the normal sleep-wake cycle

Pharmacokinetics

Absorptionabsorbed rapidly from the GI tract

peak concentrations occurring at approximately 0.75 hour

bioavailability is only 1.8%

extensive first-pass metabolism.

Pharmacokinetics

DistributionIn vitro protein binding of ramelteon is approximately 82% in human serum

mean volume of distribution after intravenous administration of 73.6 L

Metabolismprimarily of oxidation to hydroxyl and carbonyl derivatives

through the cytochrome P (CYP)-450 system

major: the CYP1A2 isoenzyme

minor: the CYP2C subfamily and CYP3A4 isoenzyme

secondary metabolism producing glucuronide conjugates

Elimination84% in urine

4% in feces

T1/2 1 to 2.6 hours

Drug interactions

fluvoxamine and other CYP450 1A2 inhibitors

rifampin and other strong CYP450 inducer

ketoconazole and other strong CYP450 3A4

inhibitors

fluconazole and other strong CYP450 2C9

inhibitors

Contraindications

Hypersensitivity to ramelteon or any components of the ramelteon formulation.

Warning

Not for use in patients with severe hepatic impairment

Hypnotics have been associated with cognitive and behavior changes, including suicidal ideation

Not recommended in patients with severe sleep apnea or severe COPD

Warning

May decrease testosterone levels and increase prolactin level

Pregnancy: category C. development toratogen in the rat

Lactation: secreted into the milk of lactating rats

Adverse EventsRamelteon Placebo

Headache 7% 7% Somnolence 5% 3% Dizziness 5% 2% Fatigue 4% 3% Nausea 3% 2% Insomnia exacerbated 3% 2% URI 3% 2% Diarrhea 2% 2% Myalgia 2% 1% Depression 2% 1% Dysgeusia 2% 1% Arthralgia 2% 1% Influenza 1% 0 Blood cortisol decreased 1% 0

Dosage and administration

8 mg PO within 30 minutes of going to bed.

NOTE: Ramelteon should not be taken with or

immediately after a high fat meal.

Storage

Store at 25°C (77°F)

Keep container tightly closed

Protected from moisture and humidity.

Clinical studies 1

An efficacy, safety, and dose–response study of Ramelteon in patients with chronic primary insomnia

Milton Erman, David Seiden, Gary Zammit, Stephen Sainati, Jeffrey Zhang

Sleep Medicine xx (2005) 1–8

Purpose

To evaluate the efficacy, safety, and dose response of Ramelteon, a novel highly selective MT1/MT2 receptor agonist, in patients with chronic primary insomnia.

Patients and methods

A randomized, multicenter, double-blind, placebo-controlled, five-period crossover study design

107 patients, aged 18–64 years randomized into a dosing sequence that included

4, 8, 16, and 32 mg of ramelteon and placebo. 5- 12day washout period between treatments administered 30 min before habitual bedtime

Patients and methods

Polysomnographic monitoring Next-day residual effects

– VAS (mood and feeling)– DSST (digit symbol substitution test)– Word-list memory tests (immediate recall and

delayed recall– Post-sleep questionnaire(alertness and ability

to concentrate)

EfficacyTable 1 PSG and subjective sleep measures

Placebo Ramelteon Overall effect

4 mg 8 mg 16 mg 32 mg

PSG latency to persistentsleep(min) 37.7 24.0*** 24.3*** 24.0*** 22.9*** P<0.001Subjective sleep latency (min) 57.0 50.9 46.7 43.9* 46.5 P=0.040PSG total sleep time (min) 400.2 411.0* 412.9** 411.2* 418.2***P=0.001Subjective total sleep time (min)360.6 364.1 370.4 370.9 372.8 P=0.282Subjective sleep quality 3.8 3.6 3.7 3.7 3.7 P=0.525PSG WASO (min) 45.5 48.8 47.0 48.3 43.0 P=0.470

Note: All data presented here are least square (LS) means. LS means are from a mixed model witheffects for sequence, subject, period of treatment, with subject as a random effect and treatment as five groups.Subjective sleep quality was measured by the post-sleep questionnaire using a 7-point scale; a lower score is better. P values for pairwise comparisons were calculated by using Dunnetts t tests from the ANOVA model of the overall treatment comparison. ***P≤0.001 for comparison of active dose with placebo. **P≤0.010 for comparison of active dose with placebo. *P≤0.050 for comparison of active dose with placebo.

Table 3Next-day performance and alertness

Placebo Ramelteon

4 mg 8 mg 16 mg 32 mg DSST 47.4 47.3 46.5 47.7 47.5

Memory test-immediate recall 8.0 7.9 7.7 8.0 7.8

Memory test-delayed recall 4.9 5.0 5.4 5.1 5.2

Level of alertness 3.6 3.5 3.6 3.5 3.6

Ability to concentrate 3.6 3.5 3.5 3.5 3.6

Note: Values represent least squares means. There were no differences between placebo and any dose group for any measure. For the DSST, a higher score is better. For the word-list memory tests, a higher score is better. For the post-sleep questionnaire, a lower score is better.

Table 4Summary of most frequently reported adverse events (%)

Placebo Ramelteon

4 mg 8 mg 16 mg 32 mg

All adverse eventsa 19.4 25.2 18.3 19.6 21.4Headache 4.9 5.8 4.8 4.7 5.8Somnolence 1.0 0.0 1.9 3.7 1.9Pharyngolaryngeal pain 1.0 3.9 0.0 0.0 3.9Nasopharyngitis 2.9 1.0 0.0 1.9 1.0Nausea 1.9 2.9 1.0 0.9 1.0Dyspepsia 0.0 1.0 0.0 0.9 2.9Influenza 2.9 1.0 1.0 0.0 0.0Abdominal pain 1.0 1.0 1.0 0.9 0.0Dysmenorrhea 0.0 1.9 1.0 0.0 1.0Dry mouth 1.0 1.9 0.0 0.0 0.0Fatigue 0.0 0.0 1.0 0.9 1.9.

Conclusions

Ramelteon demonstrated a statistically significant reduction in LPS and a statistically significant increase in TST, with no apparent next-day residual effects, in patients with chronic primary insomnia.

Clinical studies 2

Ramelteon and triazolam in human: abuse potential (abstract)

Griffiths et al. Sleep 2005

Patients and methods

placebo-controlled, crossover clinical study 14 adults with a history of polydrug or multiple-

drug abuse 7 treatment separated by a wash-out period administered to patients in a randomly-assigned

sequence and included: -ramelteon (16 mg, 80 mg, 160 mg)-triazolam (0.25 mg, 0.50 mg, 0.75 mg)-placebo.

Drug-liking

Measures of "drug-liking," were assessed each day using questionnaires completed

at intervals between 0.5 hours predose, up to 24 hours after dose administration.

Drug Liking

0

0.5

1

1.5

2

2.5

PBO0.

25 0.5

0.75 16 80 16

0

PBO

Triazolam

Ramelteon

RamelteonTriazolam

( drug Effect Questionares Scale: 0-4 )

Dru

g l

ike

P<0.05

P<0.05

Results

Triazolam treatment (0.50 mg, 0.75 mg) produced a dose-related as compared to that of placebo

Ramelteon did not produce any significant changes in drug-liking comparative to that of placebo at any dose.

patients exhibited no abuse potential at up to 20 times the proposed therapeutic dose of ramelteon

Conclusions

Ramelteon: selective melatonin receptor agonist

Provides physiological sleep via activation of MT1 receptor play a role sleep/wake cycle

8mg tablets for the treatment of insomnia characterized by difficulty with sleep onset

has no serious adverse effects including dependence, abuse ability, memory impairment and motor impairment

THE END

GABAA Agonists

Amnesia,ataxia,toleranceDependence,abuse,residual effect

Rebound insomnia,etc.

Sedative Sleep

•Dependence•Abuse•Anti-anxiety

Sedation

•Anti-epilepsy

Ataxia

Amnesia

Task performance

variety of behavioral and cognitive tasks including :

DSST

Standing balance tasks memory tests

Self-report measures of subjective drug effects are collected from the subjects using structured questionnaires. The Single-Dose Questionnaire, developed by Fraser and his coworkers (Fraser, Isbell, Martin, Van Horn, & Wolbach, 1961) is among the most elegant psychometric instruments in its simplicity and predictive power.

It contains four scales: (a) the first asks whether the drug was felt and thereby determines whether the drug is psychoactive,

(b) the second is a 14-item list of substances from which the subject is asked which the administered compound is most like and thereby permits classification (the list includes blank and other),

(c) the third is a 14-item list of sensations (including normal and high) that characterizes and quantifies symptoms, and

(d) the fourth is a 5-point liking scale which is a measure of euphoria. A similar questionnaire is completed by staff observers

แสดงขบวนการส ังเคราะห์สาร Melatonin ใน pineal gland

MelatoninDietary supplements

used most commonly for disturbances

insomnia

jet lag

Cost

Drug Interactions

PRECAUTIONS➤Monitoring: For patients presenting with unexplained

amenorrhea,galactorrhea, decreased libido, or problems with fertility, considerassessment of prolactin levels and testosterone levels as

appropriate.➤Special risk: Ramelteon has not been studied in subjects withsevere sleep apnea or severe chronic obstructive pulmonary

disease(COPD) and is not recommended for use in those populations.➤Hazardous tasks: Avoid engaging in hazardous activities thatrequire concentration (eg, operating a motor vehicle or heavy machinery) after taking ramelteon. After taking ramelteon,

patientsshould confine their activities to those necessary to prepare for

bed.

PGS

EEG electrodes electromyogram (EMG), electrooculogram

(EOG, differential recording) electrocardiogram