CLINICAL PHARMACOLOGY
Mechanism of Action:  Melatonin is a hormone synthesized in the pineal gland and, to a lesser extent, in the retina.  Melatonin’s excretion, which peaks after dark, follows a day/night rhythm not only in humans but in all species studied, and is responsible for sleep induction. The pineal gland, even at the melatonin peak levels produces minute amounts of this substance, measured in nanograms (1x10^-9 g) per ml of serum. According to Maestroni and Conti (1993) physiological concentrations of melatonin can stimulate the release of opioid peptides by activated T-helper lymphocytes.  These melatonin-induced-immuno-opioids (MIIO) mediate the immunoenhancing and anti-stress effects of melatonin and crossreact immunologically with anti-beta-endorphin and anti-met-enkaphalin antisera.  Dawson and Encel (1993) suggested that the hypnotic effect ascribed to melatonin is exerted through its effect on the thermoregulatory mechanism.  Those authors believe that by lowering core body temperature, melatonin reduces arousal and increases sleep propensity.

Metabolism: Melatonin is metabolized in the liver, which converts melatonin to 6-hydroxymelatonin, and the product is excreted in the urine as sulfate and glucuronide (Kopin et al., 1961).  The metabolism of melatonin in the central nervous system is very fast through the oxidation of melatonin to N-acetyl-5-metoxykynurenamine via N-acetyl-N-formyl-5-metoxykynurenamine (Hirata et al., 1974).
Melatonin is quickly absorbed and also quickly excreted, as evidenced by a number of clinical tests.
In a series of important studies on the bioavailability and pharmacokinetics of melatonin (Waldhauser F., et al., 1984), in which 80 mg of melatonin was administered orally to 5 young male volunteers, the peak serum melatonin levels were observed 60-150 min. after administration, and remained stable for about 90 min.  In a summary/follow up study, the same research group (Waldhauser F., Steger H. and P. Vorkapic, 1987) reported that the measured average biological half-life for the absorption from the gastrointestinal tract was 24 min., and a calculated average biological elimination half-life was 53 min., respectively.
Aldhous et al. (1985) measured the plasma concentrations of melatonin in men, fasting and fed.  A 2-mg dose gave reproducibly timed peak plasma concentrations. 30 to 60 min. after ingestion plasma melatonin remained at or above endogenous nigh-time level for 3-4 h, regardless of the subjects’ nutritional status.  The mean elimination half-lives were between 32 and 40 min.   Similar results were reported by Voordouv et al. (1992).  The peak serum level (over 100 ng/ml) after an oral administration of a single dose 75 mg to women, was observed to occur in less than 60 min.  It rapidly fell to 50% of the maximum in another 60-min. period, to reach a physiological level in about 6-8 hours after the administration.
Melatonin was administered orally to 20 healthy volunteers at 11:45 (Dollins et al.., 1993).  The mean serum melatonin levels measured starting 75 min. after the oral administration correlated well with the dosage used and were as follows:
                             Dose, mg                                 Placebo   10   20    40    80
                             Serum concentration, ng/ml            0          4     8    17    33

The serum concentration levels were reduced to only one half of those reported above after 4 hr. and 45 min.  The mean oral temperature decreased by up to 0.35 °C and was the lowest 4 hr. and 45 min. after the administration.

Highlights of Clinical Studies: Lieberman et al. (1984) studied the immediate behavioral effects of melatonin in a double-blind, placebo-controlled study on 14 young males.  They reported decreased vigor and increased fatigue and sleepiness.  The reaction time in both auditory and visual reaction tests was slower, yet the number of errors made by the subjects was reduced.  In contract to many other hypnotics, which may induce transient amnesia, memory was not affected by melatonin.
In one of the double-blind, placebo-controlled, parallel group design studies of  Waldhauser’s research group (1990), in which melatonin was administered orally at a single 80 mg dose, the following benefits of melatonin were observed: accelerated sleep initiation, improved sleep maintenance, decreased sleep stage 1 and increased sleep stage 2, and good tolerance without hangover problems on the following morning.
The influence of exogenous melatonin on the sleep-wake cycle was investigated by Dahlitz et al. (1991) by means of a randomized, double-blind, placebo-controlled trial in 8 subjects.  The subjects received a placebo or 5 mg melatonin daily for 4 weeks, at 22:00, 5 hr.  before their mean time of sleep onset.  In all 8 subjects sleep onset time (mean advance 82 min.) and wake time (117 min.) were significantly earlier on melatonin than during placebo, with unaltered alertness acrophase.
Tzischinsky, Dagan, and Lavie (1993) treated eight young patients with delayed sleep phase syndrome with 5 mg melatonin tablets administered at 19:30 for a period 4-11 weeks.  Melatonin advanced sleep time onset and wake-up time in all patients by 2 hr.
In a double blind and placebo controlled study, Dollins et al. (1994) studied the effect of small melatonin doses: 0.1-0.3 mg and 1.0-10 mg.  The former range of the orally administered melatonin raised serum melatonin concentration to within the normal nocturnal range.  Both potency ranges were shown to cause hypnotic effects, such as: a decrease in objective and self-estimated sleep-onset latency, an increase in sleep duration, and sleepiness upon awakening; relative to placebo.  All the doses studied significantly reduced oral temperature and the number of correct responses on the Wilkinson auditory vigilance test.
Three double blind and placebo-controlled experiments (Zhdanova et al., 1995) with low oral doses, 1.0, 0.3, and 0.1 mg melatonin or placebo, administered to six male volunteers showed that the sleep onset provoked by a single dose of melatonin resulted not from its effect on biological timing mechanisms, but from a direct action of the elevated circulating melatonin per se.

Tolerance: Dosages as high as 6.6 grams daily for 35 days orally (Papavasiliou et al., 1972); or 250 mg daily for 7 days, intravenously, were administered in the early studies.
The first person to ever receive 200 mg melatonin intravenously, daily for 5 days, had no evidence of any delayed toxicity or side effects 18 years later (Lerner and Nordlund, 1978).
Wright et al. (1986) have studied melatonin’s bioavailability and pharmacokinetics in man and observed no adverse side effects for doses ranging from 2 mg to 1200 mg/day.

INDICATIONS AND USAGE
QLIFE® MELATONIN , as a mild opioid, is indicated for: insomnia, sleep disorders related to the inappropriate timing of sleep and wakefulness, jet lag, adjustment to a new day or night shift for shift workers whose preceding shift was or upcoming shift is going to be a night shift, insomnia or biological clock regulation in blind patients, and sleep disruptions caused by beta-blockers and benzodiazepines.

DOSAGE (mature adults only)
Insomnia and Sleep Disorders:  The broad range of melatonin dosages from 0.1-10 mg, taken orally 20-30 min. before bedtime seem to have the desired hypnotic effect and no side effects the following day.  It is recommended that the therapy starts with a 3.0-mg dose for patients 40 years of age or older, and with a 1.0-mg for patients 18-40 years of age.  Vivid dreams, slight drowsiness, and/or any noticeable headache - either of them persisting for more than 2-3 days - indicate a possible overdose.  The difficulty with falling asleep or too short a sleep duration (less than 4 hours) indicate a possible underdose.  Should either case be experienced by a patient, the dose ought to be reduced or increased by a factor of two.  More than one adjustment may be necessary in some cases.

Jet-Lag:  The pre-flight treatment for eastward flights only: 3.0 to 6.0 mg in the late afternoon on the day preceding the flight.  The post-flight treatment: 3.0 to 6.0 mg for four days at local bedtime in a new time zone.
Shift Work:  3.0 to 6.0 mg at the desired bed time after the night shift.

PRECAUTIONS
QLIFE® MELATONIN  should not be prescribed for children below 18 years of age; breast-feeding mothers; and women who are pregnant or are trying to become pregnant.  Similarly, it should not be prescribed for the patients with auto-immune diseases or immune system cancers; severe allergies, severe depression, diabetes or other endocrine disorders.
The physicians should recommend the use of QLIFE® MELATONIN  exclusively before bedtime, and warn the patients not to drive, operate machinery, or perform tasks requiring alertness, after use.

SIDE EFFECTS
In recommended applications (20-30 min. before bedtime): vivid dreams and/or nightmares, which tend to subside with time or with lowering of a dose.
Other, also not serious, infrequent side effects were reported in trial study on jet lag (Arendt and Aldhouse, 1988)  52 subjects were given melatonin or placebo:  8% reported headache and nausea (vs. 4% and 2%, respectively, placebo), 6% gastrointestinal problems (4% on placebo).  In a very large study on jet lag (Arendt et al., 1995) with 586 subjects taking 5 mg melatonin, the following side effects were observed (melatonin % vs placebo %): sleepiness (8.3 vs 1.8), headache (1.7 vs 2.7), nausea (0.8 vs 0.9), light-headedness (0.8 vs 0), and "fuzziness/giddiness" (0.6 vs 0).
In day-time applications, self-rated fatigue (tiredness), sleepiness, and hostility have been reported.

HOW SUPPLIED
QLIFE® MELATONIN  3 mg tablets are round-shaped, white, compressed tablets; two grooves divide each tablet into quarters.  The tablets are available in bottles of 60.  Each bottle is double-sealed and contains desiccant for safety and additional stability.

Storage:  Store at room temperature 15°C -30°C (60°F -85°F).

REFERENCES

Aldhous M. et al., Br. J. Clin. Pharmacol., 19(4), 517-21 (1985)
Arendt J. and M. Aldhous, Annu. Rev. Chronopharmacol, 5, 53-55 (1988)
Arendt J. et al., J. Sleep Res., 4(s.2), 74-79 (1995)
Dahlitz M. et al., The Lancet, 337, 1121-1124 (1991)
Dawson D. and N. Encel,  J. Pineal Res., 15(1), 1-12 (1993)
Dollins A.R., Psychopharmacology, 112, 490-496 (1993)
Dollins A.R., Proc. Natl. Acad. Sci USA, 91, 1824-1828 (1994)
Hirata F. et al., J. Biol. Chem.,  249, 1311-1313 (1974)
Kopin I.J., et al., J. Biol. Chem., 236, 3072-3075 (1961)
Lerner A.B. and J.J. Nordlund, J. Neural Transmission, Suppl. 13, 339-347 (1978)
Lieberman H.R. et al., Brain Res., 323, 201-207 (1984)
Maestroni G.J.M. and A. Conti, Melatonin and the pineal gland - From basic science to clinical
application, pp. 295-302, Touitou Y. , Arendt J. and P. Pevet (eds), Elsevier Science Publ., 1993
Papavasiliou P.S. et al.,  JAMA, 221(1), 88 (1972)
Tzischinsky O., Dagan Y, and P. Lavie, Melatonin and the pineal gland - From basic science to clinical application, pp. 351-354, Touitou Y. , Arendt J. and P. Pevet (eds), Elsevier Science Publ., 1993
Voordouw B.C.G. et al., J. of Clinical Endocrinology & Metabolism, 74, 108-117  (1992)
Waldhauser F. et al., Neurocrinology, 39, 307-313 (1984)
Waldhauser F., Steger H., and P. Vorkapic, Advances in pineal research: 2, pp. 207-221, Reiter R.J. and F. Fraschini (eds), John Libbey & Co. Ltd., 1987
Waldhauser F., Saletu B. and I. Trinchard-Lugan, Psychopharmacology, 100, 222-226 (1990)
Wright J. et al., Clin. Endocrinol. 24,  375-381 (1986)
Zhdanova I.V. et al., Clin. Pharmacology & Therapeutics, 57(5), 552-558 (1995)
 

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