Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (aswpd), delayed sleep-wake phase disorder (dswpd), non-24-hour sleep-wake rhythm disorder (n24swd), and irregular sleep-wake rhythm disorder (iswrd): an update for 2015

A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed.

Treatment of climacteric symptoms in survivors of gynaecological cancer.

Different treatments (surgery, radiotherapy, chemotherapy) for gynaecological cancers may cause ovarian failure or increase menopausal symptoms. There is a widespread reluctance among physicians to prescribe hormone replacement therapy (HRT) to the survivors of gynaecological cancer. This review analyses the use of HRT and of alternative therapies in such women. Squamous cervical cancer is not estrogen dependent and thus HRT is not contraindicated. While a cautious approach to hormone-dependent cancer is warranted, for women treated for non-hormone-related tumours alternative treatments for menopausal symptoms should be given due consideration, as any reluctance to prescribe HRT for them has neither a biological nor a clinical basis. In studies of HRT for survivors of endometrial and ovarian cancer, for instance, no evidence of increased risk was found, although no definitive conclusions can yet be formulated. The positive effect of HRT on quality of life seems to outweigh the unfounded suspicion of an increased risk of recurrence of non-hormone-related tumours. Effective non-hormonal alternatives for vasomotor symptoms are selective serotonin reuptake inhibitors and selective serotonin-norepinephrine reuptake inhibitors.

Common questions about the diagnosis and management of fibromyalgia.

Fibromyalgia has a distinct pathophysiology involving central amplification of peripheral sensory signals. Core symptoms are chronic widespread pain, fatigue, and sleep disturbance. Most patients with fibromyalgia have muscle pain and tenderness, forgetfulness or problems concentrating, and significant functional limitations. Fibromyalgia is diagnosed using an updated set of clinical criteria that no longer depend on tender point examination; laboratory testing may rule out other disorders that commonly present with fatigue, such as anemia and thyroid disease. Patients with fibromyalgia should be evaluated for comorbid functional pain syndromes and mood disorders. Management of fibromyalgia should include patient education, symptom relief, and regular aerobic physical activity. Serotoninnorepinephrine reuptake inhibitors, tricyclic antidepressants, antiepileptics, and muscle relaxants have the strongest evidence of benefit for improving pain, fatigue, sleep symptoms, and quality of life. Multiple complementary and alternative medicine therapies have been used but have limited evidence of effectiveness. Opioids should be used to relieve pain in carefully selected patients only if alternative therapies are ineffective.

[Orexin: clinical and therapeutic implications]. / Orexina: implicaciones clínicas y terapéuticas.

INTRODUCTION. Recent research has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. DEVELOPMENT. This fuzzy pattern of distribution of the orexinergic fibres would be indicating the involvement of this peptidic system in a wide range of functions; indeed, it has been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning, such as learning certain preferences regarding tastes. It has also been suggested that upsets in the functioning of the orexinergic system would explain the appearance of certain clinical disorders like narcolepsy, obesity or addiction to drug of abuse. CONCLUSIONS. Further research will help to determine the functioning of orexinergic neurons and the interaction between the systems that regulate emotion, energetic homeostasis and the reward mechanisms, on the one hand, and the systems that regulate the sleep-wake cycle on the other. That knowledge would almost certainly make it possible to develop new drugs that, by acting upon the orexinergic system, would be effective in the treatment of sleep disorders such as insomnia or narcolepsy, eating disorders or drug addiction.

TITLE: Orexina: implicaciones clinicas y terapeuticas.Introduccion. Se ha descrito recientemente una nueva clase de neuropeptidos, las orexinas, tambien llamadas hipocretinas, producidos por un reducido grupo de neuronas hipotalamicas y cuyas acciones son mediadas por dos tipos de receptores, OX1R y OX2R. En concreto, las neuronas orexinergicas se han localizado en exclusiva en celulas de areas del hipotalamo lateral, dorsomedial y perifornical. A pesar de este origen anatomico tan localizado, las neuronas orexinergicas se proyectan ampliamente a numerosas regiones troncoencefalicas, corticales y limbicas. Desarrollo. Este patron difuso de distribucion de las fibras orexinergicas estaria indicando la intervencion de este sistema peptidico en una amplia variedad de funciones y, de hecho, se ha relacionado con los mecanismos que permiten la regulacion del ciclo sueño-vigilia, la ingesta de comida y de bebida y determinados aprendizajes como el aprendizaje de preferencias gustativas. Se ha sugerido tambien que la alteracion en el funcionamiento del sistema orexinergico explicaria la aparicion de determinados trastornos clinicos como la narcolepsia, la obesidad o la adiccion a drogas de abuso. Conclusiones. Nuevas investigaciones ayudaran a conocer el funcionamiento de las neuronas orexinergicas y la interaccion entre los sistemas que regulan la emocion, la homeostasis energetica y los mecanismos de recompensa con los sistemas que regulan el ciclo de sueño-vigilia. Se confia en que ese conocimiento permita desarrollar nuevos farmacos que, actuando sobre el sistema orexinergico, sean eficaces en el tratamiento de las alteraciones del sueño como el insomnio o la narcolepsia, de los trastornos de la alimentacion o de la drogadiccion.

Hypnic headache: a review of 2012 publications.

Hypnic headache is a rare primary headache disorder affecting middle age and above with a dull pain exclusively at nighttime. This article aims to review and discuss the most recent articles published in the year 2012 regarding hypnic headache. We will also discuss specific cases of pharmacological and nonpharmacologic successes in treating this rare disorder.

Hallucinations and sleep disturbances in Parkinson's disease.

Visual hallucinations (VHs) occur frequently in Parkinson's disease (PD). VHs occur more frequently in elderly patients with longer duration of illness, cognitive impairment, and sleep disturbances. The relationship between the use of antiparkinsonian drugs and VHs is complicated, but most drugs used to treat parkinsonian motor symptoms induce VHs and psychosis in some PD patients. The "continuum hypothesis" proposing that medication-induced psychiatric symptoms in PD begin with drug-induced sleep disturbances, followed by vivid dreams, with progression to hallucinatory and delusional experiences has been challenged. In some patients, VHs may represent intrusion of REM sleep-related imagery into wakefulness. Improving REM sleep abnormalities in PD (e.g., stimulants, anticholinesterase inhibitors) is one strategy now being tested to improve VHs in PD.

Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals.

In blind individuals, the absence of light cues results in disturbances of sleep and sleep-related neuroendocrine patterns. The Zeitgeber influence of light on the timing of sleep is assumed to be mediated by melatonin, a hormone of the pineal gland, whose secretion is inhibited by light and enhanced during darkness. Here, we investigated whether a single administration of melatonin improves sleep and associated neuroendocrine patterns in blind individuals. In a double-blind crossover study, 12 totally blind subjects received 5 mg melatonin and placebo orally 1 h before bedtime starting at 2300 h. The dose used enhanced blood melatonin concentrations to clearly supraphysiological levels. Melatonin increased total sleep time and sleep efficiency (P < 0.05, respectively) and reduced time awake (P < 0.05). The increment in total sleep time was primarily due to an increase in stage 2 sleep (P < 0.01) and a slight increase in rapid eye movement sleep (P < 0.06). Most important, melatonin normalized in parallel the temporal pattern of ACTH and cortisol plasma concentration. While after placebo, ACTH and cortisol levels did not differ between early and late sleep, melatonin induced the typical suppression of pituitary-adrenal activity during early sleep and a distinct rise during late sleep (P < 0.01, respectively). Cortisol nadir values were also decreased after melatonin (P < 0.05). We conclude from these data that in totally blind individuals the single administration of a clearly pharmacological dose of melatonin can improve sleep function by synchronizing in time the inhibition of pituitary-adrenal activity with central nervous sleep processes.

Kava and valerian in the treatment of stress-induced insomnia.

Kava and valerian are herbal remedies, claimed to have anxiolytic and sedative properties respectively, without dependence potential or any appreciable side-effects. In this pilot study, 24 patients suffering from stress-induced insomnia were treated for 6 weeks with kava 120 mg daily. This was followed by 2 weeks off treatment and then, 5 having dropped out, 19 received valerian 600 mg daily for another 6 weeks. Stress was measured in three areas: social, personal and life-events; insomnia in three areas also: time to fall asleep, hours slept and waking mood. Total stress severity was significantly relieved by both compounds (p < 0.01) with no significant differences between them; as was also insomnia (p < 0.01). The proportion of patients with no side-effects was 58% with each drug respectively and the 'commonest' effect was vivid dreams with valerian (16%), followed by dizziness with kava (12% ). These compounds may be useful in the treatment of stress and insomnia but further studies are required to determine their relative roles for such indications.