Preface

The pineal hormone of "darkness," melatonin (*N*-acetyl-5-methoxytryptamine), is biosynthesized and secreted mainly at night. It is an important component in the regulation of seasonal and circadian rhythms. Its action is believed to be mediated through a family of specific, high-affinity, G-protein-coupled cell membrane receptors. It is ubiquitous throughout both the animal and plant kingdoms and must have a long evolutionary history as a hormone. The secretion of the hormone is closely synchronized with the habitual hours of sleep in humans. Ingestion of melatonin affects sleep propensity as well as duration and quality of sleep. Sleep problems become more common in the elderly in whom there is also a loss in the production of melatonin.

Melatonin treatment has therapeutic value in some blind subjects, restoring their disturbed circadian rhythm. It also has potential in the treatment of seasonal affective disorder (SAD), which afflicts some people during the short winter days, and it has been used to reset the clock in sufferers from jet lag. Melatonin has been implicated in a range of other conditions, including Parkinson's disease, Alzheimer's and other neurodegenerative conditions, and in certain cancers. It has also recently been shown that melatonin can be synthesized by mammalian skin, where it may be important in regulating hair growth and pigmentation physiology.

Several synthetic molecules have shown interesting melatoninergic activity, frequently greater and more selective than that of the endogenous hormone. Ramelteon was the first prescription medication for insomnia, and the only hypnotic indicated for longterm treatment of insomnia as it does not have hangover, addictive, or withdrawal effects. Another melatonin analogue, agomelatine, has recently been introduced as an antidepressant and appears to have few side effects.

The use of melatonin as a drug is hampered by its short biological half-life and poor bioavailability. As a result, dosage forms, which mimic the physiologically secreted melatonin concentration versus time model, are limited.

The eight chapters in this book deal with all these aspects. The initial chapter provides an account of most of the synthetic melatoninergic agents available thus far, and is addressed to a wide non-cognizant readership. Briefly, this chapter focuses on the synthetic routes towards synthetic melatonin derivatives, first of their aromatic nucleus, then of the functionalities that have been introduced to the nucleus, and finally those analogues with restrained conformations and those that are optically active. The second chapter is pivotal to the research on melatonin's direct involvement with sleep and the dysfunctions caused by insomnia, which are also presented in the third chapter. Moreover, in the latter chapter, the use of synthetic melatonin, as a food supplement in various dosage forms such as pills, granules for oral solution, orodispersable granules, and syrups in order to address patients' needs, is described. The fourth chapter focuses on the electrophysiological and the antiarrhythmic properties of melatonin. The acute and chronic protective mechanisms of melatonin are analyzed with an emphasis on transmembrane potentials and intercellular communication. An outstanding antifibrilatory effect

**II**

**Section 5**

**Section 6**

Depression

Review of Melatonin in Horticultural Crops *by Yanyan Yan, Qinghua Shi and Biao Gong*

Melatonin's Physiological Functions in Plants **105**

**Chapter 7 107**

Effect of Melatonin on 5-HT Active Transport **131**

**Chapter 8 133**

Studies on Tryptophan Metabolites in Patients of Major Monopolar

*by Hiroi Tomioka, Junichi Masuda, Akikazu Takada and Akira Iwanami*

is claimed to make melatonin a novel antiarrhythmic agent worthy of further exploration in the path to clinical applications. In the context of the fifth chapter, a review of the related literature on the modified release of melatonin from its *per os* administered formulations is presented, including utilization of design of experiments (DoE) for the selection of the optimal composition of melatonin formulations. The chapter offers an account of the recent advantages on the hormone's solid dosage forms suitable for treating sleep disorders, referring either to its onset or maintenance. The sixth chapter describes the conventional solid and liquid forms (i.e., tables, capsules, suspensions, etc.) and the nanoformulations (i.e., liposomes, niosomes, polymeric nanoparticles, chitosomes, calcium alginate beads, etc.) of melatonin, focusing on its release kinetics from pharmaceutical vehicles. These systems have been designed and developed as platforms for the delivery and release of melatonin. The penultimate chapter describes melatonin's physiological functions, including regulating plant growth, promoting seed germination, controlling root development and delaying leaf senescence. The final chapter refers to the active transport of 5-HT by platelets, which has been shown to be significantly correlated with melatonin blood levels. This expounds either a direct effect of melatonin on 5-HT active transport or the influence of the suprachiasmatic nucleus on serotonin uptake by platelets, pathways that are considered to be associated with various neurobiological alterations, like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity, and altered circadian rhythms.

*Acknowledgements*. I would like to thank all the authors, who contributed to the compilation of this text: Professor Andrew Tsotinis and Ass. Professor Ioannis Papanastasiou (Chapter 1); Dr. Alexander Zakharov (Chapter 2); Ms. Ioulia K. Tseti, MSc (Chapter 3); Ms. Natalia Jorgelina Prado, Dr. Margarita Segovia-Roldan, Dr. Emiliano Raúl Diez, Professor Esther Pueyo (Chapter 4); Dr. Angeliki Siamidi and Ass. Professor Yannis Dotsikas (Chapter 5); Dr. Natassa Pippa and Professor Costas Demetzos (Chapter 6); Yanyan Yan, Professor Qinghua Shi, Professor Biao Gong (Chapter 7); Dr. Hiroi Tomioka, Junichi Masuda MD, Dr. Akikazu Takada, Ms. Akira Iwanami (Chapter 8).
