Research & Development Melatonin: Regulating the biological clock The natural hormone melatonin (N-acetyl-5-methoxytryptamin) is produced by the pineal gland, located in the human brain. Production especially takes place by night. Secretion is stimulated by the dark and inhibited by light. In a cascade of reactions, the amino acid tryptophan is converted to serotonin, which in turn is converted to melatonin. The influence of melatonin on the "circadian" rhythm ("biological clock") is probably related to the presence of melatonin receptors on the suprachiasmatic nuclei (SCN) of the hypothalamus. Research into the role of melatonin plasma levels in a variety of disorders and diseases has made it clear that there are numerous biological processes (in humans and animals) that are either affected by changes in melatonin plasma levels or are the cause of those changes. Applications of melatonin   Sleep disorders and jet-lag Travel at rapid rates across time zones disturbs the body" natural circadian rhythm leading to sleep disturbance, reduced psychomotor efficiency, loss of appetite and a general feeling of malaise. In other words: jet-lag. To alleviate the symptoms of jet-lag and support the body to more quickly adapt to the new time zone, melatonin is regularly used by pilots and in-flight crews on long distance flights. It appears from different studies that taking melatonin for several days on arrival is the most beneficial. Significant faster recovery of energy and alertness was observed, combined with less impact from mood swings and sleepiness. To counter the effect of sleep disturbances when working shifts, the use of melatonin has been studied in shift workers. When taking melatonin at bedtime, increased alertness in waking hours was observed. Physiological sleep onset probably involves nocturnal melatonin secretion. Exogenous melatonin may therefore by useful in treating insomnia. Studies showed no "hangover" effects when taking small doses of melatonin around the time of endogenous melatonin release and habitual sleep onset. Related to the topics mentioned above, melatonin is also used in treating adults with Delayed Sleep Phase Syndrome and in blind people who suffer from free-running sleep/wake rhythm. In children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD), melatonin showed good results in decreasing sleep delay. Children that are neurologically multiple disabled often exhibit poor sleeping patterns. Melatonin given at bedtime resulted in improved sleeping patterns, in turn leading to behavioral and social benefits. Scientific publications Carr R, Wasdell MB, Hamilton D, Weiss MD, Freeman RD ,Tai J. Rietveld WJ, Jan JE. Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm disorders. J Pineal Res 2007, 43(4): 351-359 Cohen M, Small RA, Brzezinski A. Hypotheses: melatonin / steroid combination contraceptives will prevent breast cancer. Breast Cancer Res Treat 1995; 33(3): 257-264 Cohen M, Josimovich J, Brzezinski A. Melatonin: From Contraception to Breast Cancer Prevention. Sheba Press Ltd. Potomac. "1995, 1996. ISBN 1-880613-10-7 Jan JE, Wasdell MB, Freeman RD, Bax M. Evidence supporting the use of melatonin in short gestation infants. J Pineal Res, 2007, 42(1): 22-7. Jan JE, Wasdell MB, Reiter RJ, Weiss MD, Johnson KP, Ivanenko A, Freeman R. Melatonin therapy of pediatric sleep disorders: recent advances, Why it works, Who are the candidates and how to treat. Current Pediatric Reviews, 2007, 3: 214-224 Jan JE, Wasdell MB, Weiss MD, Freeman RD. What is the correct dose of melatonin in sleep therapy. Letter to the editor. Biol Rhythm Res, 38 (2): 85-87 Voordouw ACG, Euser R, Verdonk HER, Alberda BT, Jong de FH, Drogendijk AC, Fauser BCJM, Cohen M. Melatonin and melatonin-progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinology Metabol 1992; 74(1): 108-117 Wasdell MB, Jan JE, Bomben MM, Freeman RD, Rietveld WJ, Tai J, Hamilton D, Weiss MD. A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res, 2008 Jan; 44(1):57-64. Weiss MD, Wasdell MB, Bomben MM, Rea KJ, Freeman RD. Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry 2006; 45(5): 512-519 Clinical trials Ninotalem" has proven to be safe and effective as treatment of circadian rhythm related sleep disorders in clinical trials with special (patient) populations. Multi-disabled children who often experience poor sleep patterns were treated with Ninotalem" in a randomized placebo-controlled cross-over  study. Ninotalem"  showed both a significant decrease in sleep-delay and  an improved sleep pattern.  In a long-term open label study with Ninotalem", this improvement was maintained, which also had a positive effect on overall well-being of both children and their caretakers. Children with a ADHD-diagnosis who suffered from sleep disorders that did not respond to sleep hygiene were treated with Ninotalem" in a randomized, placebo controlled cross-over study. Sleep-delay was significantly decreased by Ninotalem" 5 mg tablet. Other sponsored clinical trials have demonstrated the safety of Circa Dia"s melatonin in populations encompassing over 1,000 subjects up to a dosage as high as 300 mg daily (Voordouw et al. 1992). Ninotalem" is offered as a 5 mg tablet, which equals the daily dosage for the treatment of different indications. Circa Dia IP portfolio Circa Dia has been granted two patents in which Ninotalem" is claimed to have a decreasing effect on sleep-delay in humans with ADHD. Use of Melatonin & ADHD 1) WO2002EP03317 (EP1370259) Use of Melatonin in the Manufacture of a Medicament for treating Attention Deficit Hyperactive Disorder Granted Claims:    1. Use of at least one of melatonin, a melatonin analogue, or a pharmaceutically acceptable salt of melatonin or said melatonin analogue, in the preparation of a medicament for the treatment of AHDH in mammals, especially a human being.    2. Use as claimed in claim 1 wherein the melatonin or melatonin analogue is employed in an amount of from 0.005 to 1.00 mg/kg in treating ADHD.    3. Use as claimed in any one of the preceding claims wherein the medicament is formulated as a controlled release preparation.    4. Use as claimed in any one of the preceding claims wherein the medicament is formulated as a solid oral formulation.    5. Use as claimed in any one of the preceding claims wherein the medicament additionally contains one or more substances selected from the group of stimulants, hormones, analogues of such hormones, phyto-hormones, analogues of such phyto-hormones, and anti-oxidants.    6. A method of preventing or treating ADHD disorder in a mammal, in particular a human, which comprises administering to said mammal a therapeutically effective amount of melatonin, a melatonin analogue, or a pharmaceutically acceptable salt of melatonin or said melatonin analogue. Combined Use of Melatonin 2) WO 2004/028532 (EP1545511) Combined Use of Methylphenidate and Melatonin for treating Attention-Deficit Hyperactive Disorder Granted Claims:    1. Use of methylphenidate and at least one of melatonin, a melatonin analogue, or one or more pharmaceutically acceptable salts or esters thereof, in the preparation of a medicament for the treatment of ADHD in a mammal, especially a human being.    2. Use as claimed in claim 1 wherein the melatonin or melatonin analogue is employed in an amount of from 0.005 to 1.00 mg/kg in treating ADHD.    3. Use as claimed in any one of the preceding claims wherein the medicament is formulated as a controlled release preparation.    4. Use as claimed in any one of the preceding claims wherein the medicament is formulated as a solid oral formulation.    5. Use as claimed in any one of the preceding claims wherein the medicament additionally contains one or more substances selected from the group of stimulants, hormones, analogues of such hormones, phyto-hormones, analogues of such phyto-hormones, and anti-oxidants.    6. A method of preventing or treating ADHD disorder in a mammal, in particular a human, which comprises administering to said mammal a therapeutically effective amount of methylphenidate and one of melatonin, a melatonin analogue, or one or more pharmaceutically acceptable salts or esters thereof.    7. A method as claimed in claim 6, wherein methyl phenidate and melatonin are applied simultaneously.    8. A method as claimed in claim 6, wherein methyl phenidate and melatonin are applied subsequently.    9. A method as claimed in claim 8, wherein melatonin is administered following the administration of methyl phenidate.   10. A pharmaceutical composition, comprising, as active ingredients, methylphenidate and at least one of melatonin, a melatonin analogue, or one or more pharmaceutically acceptable salts or esters thereof, in conjunction with a pharmaceutically acceptable carrier.   11. A pharmaceutical composition according to claim 10 comprising, as active ingredients, methylphenidate and melatonin, in conjunction with a pharmaceutically acceptable carrier.   12. Use of methylphenidate and at least one of melatonin, a melatonin analogue, or one or more pharmaceutically acceptable salts or esters thereof as claimed in claim 1, wherein methylphenidate and at least one of melatonin, a melatonin analogue, or one or more pharmaceutically acceptable salts or esters thereof are comprised in separate forms of administration. For the marketing of its product Ninotalem", Circa Dia seeks alliances with Academic Research Groups in order to combine efforts in marketing melatonin for children and adults who suffer from sleeping disorders that are either caused by AHDH or by the use of its medication methylphenidate (Ritalin either immediate or slow release or Concerta). Side effects of this medication include sleeping disorders, which can be significantly reduced when Ninotalem" is taken before bedtime.