RESUMEN

BACKGROUND: Alzheimer's disease (AD) is an age-dependent neurodegenerative disease with progressive cognition and memory loss, insomnia, and other abnormal behavioral changes. Amongst various hypotheses for AD pathophysiology, occupational stress-induced Alzheimer's has recently been reported in many AD cases. OBJECTIVE: Studies pertaining to the same suggest that stress leads to insomnia or sleep disruption, which further leads to neuroinflammation due to oxidative stress, both of which are major harbingers of AD. Additionally, overall sleep deficit is associated with progressive cognitive and memory decline, which adds more inconvenience to Alzheimer's disease. Based on this, any triumphant AD management needs a pharmacological intervention that can not only antagonize the amyloid betainduced neurotoxicity but also correct the sleep-wake cycle disruption. Chronobiotic therapeutics like melatonin offer vital neuroprotective effects by eliciting its action through more than one of the pathologies of AD. This is also bolstered by the finding that endogenous melatonin levels are lower in AD patients. This melatonin replacement therapy can be especially useful in AD treatment, but only in the early phases of the disease and in cases where the melatonin receptors are intact and functioning. CONCLUSION: To negate such limitations and extend the action and therapeutic efficacy of melatonin- mediated actions towards AD treatment, melatonin analogue like tasimelteon can pose a high therapeutic value in AD treatment superior to that provided by melatonin. This review encapsulates all details about how AD is believed to occur and how current situations influence it, along with how melatonin and tasimelteon act towards treating Alzheimer's.

Asunto(s)

Enfermedad de Alzheimer , Melatonina , Enfermedades Neurodegenerativas , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Melatonina/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico

RESUMEN

Jet Lag Disorder is a Circadian Rhythm Sleep-Wake Disorder resulting from a misalignment of the endogenous circadian clock and the sleep and wake pattern required by a change in time zone. Jet lag is most severe following eastward travel. This multicenter, randomized, placebo-controlled clinical trial (JET) assessed the physiological mechanism of jet lag induced by a real-life transmeridian flight and evaluated the efficacy of tasimelteon-a circadian regulator acting as a dual melatonin receptor agonist, in the treatment of Jet Lag Disorder (JLD). Tasimelteon-treated participants slept 76 min longer on Night 3 during their second trip (evaluation phase) as compared to their first (observational phase). Over the three travel nights evaluated, transmeridian jet travelers in the tasimelteon group slept 131 min more (TST2/3) than those in the placebo group. The JET study demonstrated clinically meaningful improvements in nighttime sleep and daytime alertness in both objective and subjective measures as well as global functioning after a real-world flight. These results suggest that tasimelteon can be an effective therapeutic tool to treat JLD in the context of transmeridian travel.

RESUMEN

Melatonin is a human neurotransmitter and plant signalling metabolite that perceives and directs plant metabolism. The mechanisms of melatonin action in plants remain undefined. We hypothesized that roots have a melatonin-specific receptor and/or transporter that can respond to melatonin-mediating pharmaceuticals. To test this hypothesis Arabidopsis seedlings were grown with melatonin pharmaceutical receptor agonists: ramelteon and tasimelteon, and/or antagonists: luzindole and 4-P-PDOT. Ramelteon was found both to mimic and competitively inhibit melatonin metabolism in plants. Due to the higher selectivity of ramelteon for the MT1 receptor type in humans, a sequence homology search for MT1 in Arabidopsis identified the rhomboid-like protein 7 (RBL7). In physiological studies, Arabidopsis rbl7 mutants were less responsive to ramelteon and melatonin. Quantum dot visualizations of the effects of ramelteon on melatonin binding to root cell membranes revealed a potential mechanism. We propose that RBL7 is a melatonin-interacting protein that directs root architecture and growth in a mechanism that is responsive to environmental factors.

Asunto(s)

Arabidopsis , Melatonina , Animales , Arabidopsis/genética , Arabidopsis/metabolismo , Humanos , Mamíferos/metabolismo , Melatonina/farmacología , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/agonistas , Receptor de Melatonina MT2/metabolismo

RESUMEN

In mammals, including humans, the neurohormone melatonin is mainly secreted from the pineal gland at night and acts on two high-affinity G protein-coupled receptors, the melatonin MT1 and MT2 receptors. Major functions of melatonin receptors in the brain are the regulation of circadian rhythms and sleep. Correspondingly, the main indications of the currently available drugs for these receptors indicate this as targets. Yet these drugs may not only improve circadian rhythm- and sleep-related disorders but may also be beneficial for complex diseases like major depression, Alzheimer's disease, autism, and attention-deficit/hyperactivity disorders. Here, we will focus on the hypothalamic functions of melatonin receptors by updating our knowledge on their hypothalamic expression pattern at normal, aged, and disease states, by discussing their capacity to regulate circadian rhythms and sleep and by presenting the clinical applications of the melatonin receptor-targeting drugs ramelteon, tasimelteon, and agomelatine or of prolonged-release melatonin formulations. Finally, we speculate about future trends in the field of melatonin receptor drugs.

Asunto(s)

Trastorno Depresivo Mayor , Melatonina , Anciano , Animales , Encéfalo/metabolismo , Ritmo Circadiano , Humanos , Melatonina/uso terapéutico , Receptor de Melatonina MT1/metabolismo

RESUMEN

Introduction: Melatonin, a hormone that regulates circadian rhythms and the sleep-wake cycle, is produced mainly during the dark period in the pineal gland and is suppressed by light exposure. Patients with non-24-h sleep-wake disorder (non-24) fail to entrain the master clock with the 24-h light-dark cycle due to the lack of light perception to the suprachiasmatic nucleus typically in totally blind individuals or other organic disorders in sighted individuals, causing a progressive delay in the sleep-wake cycle and periodic insomnia and daytime sleepiness.Areas covered: Herein, the authors review the pharmacological therapies including exogenous melatonin and melatonin receptor agonists for the management of non-24. They introduce a historical report about the effects of melatonin on the phase shift and entrainment for blind individuals with the free-running circadian rhythm.Expert opinion: Orally administered melatonin entrains the endogenous circadian rhythm and improves nighttime sleep and daytime alertness for non-24. Currently, tasimelteon is the only approved medication for non-24 by the US Food and Drug Administration and the European Medicines Agency. Treatments that focus only on sleep problems are insufficient for the treatment of non-24, and aids to entrain the free-running rhythm with the light-dark cycle are needed.

Asunto(s)

Melatonina , Trastornos del Sueño del Ritmo Circadiano , Trastornos del Sueño-Vigilia , Ritmo Circadiano , Humanos , Melatonina/uso terapéutico , Sueño , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico

RESUMEN

Novel stability-indicating HPLC methods have been presented for the analysis of Tasimelteon (TSM) besides its main degradation products in bulk and pseudo tablet formulations in this study. For the LC-DAD method; quantitation of TSM and its separation with other degradation products were achieved on an Ascentis ExpressTM pentafluorophenylpropyl (F5)-bonded fused-core silica particle column (2.7 µm particle size 100 × 4.6 mm, Supelco) using the mobile phase consisted of acetonitrile: acetate buffer (0.025 M, pH 4.5): water (40:10:50, v/v/v); the elution was performed at 0.8 mL min-1 flow rate, detecting the compounds at 281 nm. In addition to regular in- house validation studies, the developed method was tested on another UPLC instrument to assess its ruggedness for possible method transfer demands. For the LC-MS/MS method, analyte quantitation was achieved on a second-generation monolithic silica column (Chromolith™ High-Resolution RP-18e, 100 × 4.6 mm from Merck KGaA, Germany); the mobile phase was a mixture with 0.1 % (v/v) formic acid in water and 0.1 % (v/v) formic acid in acetonitrile (60: 40 (v/v), pH = 2.5). The instrumental and analytical performances of all three instrumental systems were compared with each other in terms of the working range, LOD, and LOQ. In addition to the above, a new degradation product was identified using LCMS-IT-TOF system. It can be concluded that among the similar ones in the literature, this study is the most comprehensive method optimization and validation study to date about TSM, in which a novel degradation product was also reported.

Asunto(s)

Espectrometría de Masas en Tándem , Benzofuranos , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Ciclopropanos , Alemania , Reproducibilidad de los Resultados

RESUMEN

Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness. Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201. Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive tasimelteon (n = 160) or placebo (n = 160). Tasimelteon treatment increased TST2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by -15.1 min (95% CI -26.2 to -4.0, P = 0.0081). Conclusion: A single dose of tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.

Asunto(s)

Diarrea/tratamiento farmacológico , Mordeduras y Picaduras de Insectos/tratamiento farmacológico , Malaria/tratamiento farmacológico , Enfermedad Relacionada con los Viajes , Viaje , Animales , Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Diarrea/metabolismo , Diarrea/microbiología , Humanos , Mordeduras y Picaduras de Insectos/metabolismo , Mordeduras y Picaduras de Insectos/microbiología , Malaria/diagnóstico , Malaria/metabolismo

Asunto(s)

Mal de Altura/tratamiento farmacológico , Antieméticos/uso terapéutico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Síndrome Jet Lag/tratamiento farmacológico , Mareo por Movimiento/tratamiento farmacológico , Acetazolamida/uso terapéutico , Mal de Altura/diagnóstico , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Dexametasona/uso terapéutico , Humanos , Síndrome Jet Lag/diagnóstico , Modafinilo/uso terapéutico , Mareo por Movimiento/diagnóstico

RESUMEN

We present a totally blind adolescent with refractory insomnia due to a combination of Non-24 hour sleep-wake disorder and restless leg syndrome that was successfully treated with tasimelteon, iron replacement, and gabapentin. To our knowledge, this is the first published report of treatment of N24 with tasimelteon in an adolescent. In addition, this case highlights the importance of recognizing and treating multifactorial causes of insomnia.

Asunto(s)

Ceguera/complicaciones , Síndrome de las Piernas Inquietas/complicaciones , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Adolescente , Benzofuranos/administración & dosificación , Benzofuranos/uso terapéutico , Ciclopropanos/administración & dosificación , Ciclopropanos/uso terapéutico , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Gabapentina/administración & dosificación , Gabapentina/uso terapéutico , Humanos , Hierro/administración & dosificación , Hierro/uso terapéutico , Trastornos del Sueño del Ritmo Circadiano/complicaciones , Trastornos del Sueño del Ritmo Circadiano/fisiopatología

RESUMEN

Melatonin and melatonin agonists offer novel treatments for sleep and mood disorders, particularly where circadian misalignment is also present. The therapies offer both phase-shifting and sleep-promoting effects and have shown potential to treat advanced and delayed sleep-wake phase disorder, non-24-h sleep-wake cycle, jetlag, shift work disorder, insomnia, seasonal affective disorder and major depressive disorder.

Asunto(s)

Trastorno Depresivo Mayor , Melatonina , Trastornos del Inicio y del Mantenimiento del Sueño , Ritmo Circadiano , Humanos , Trastornos del Humor , Sueño , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico

RESUMEN

INTRODUCTION: Non-24-h sleep-wake rhythm disorder (non-24) is observed in approximately half of totally blind individuals, a condition caused by their circadian pacemaker in the suprachiasmatic nucleus not being entrained to 24 h due to a lack of light perceptions. These subjects have a progressively delayed circadian cycle each day, non-24 periodically inducing nighttime insomnia and daytime sleepiness. Tasimelteon is a dual melatonin receptor agonist with high affinity for the melatonin 2 receptor, and it entrains endogenous melatonin rhythms and sleep-wake cycles in individuals with non-24. Areas covered: Herein, the authors review the treatment of non-24 with tasimelteon. The authors further compare tasimelteon with other melatonin receptor agonists. Expert opinion: The treatment strategies for non-24 aim to resynchronize the free-running rhythm with the 24 h light-dark cycle. Tasimelteon entrains circadian rhythms and improves the sleep-wake functions of individuals with non-24. Furthermore, the RESET study demonstrated that 20% of patients that discontinued tasimelteon maintained circadian entrainment whereas 90% of those who continued it maintained circadian entrainment. Long-term administration of tasimelteon is safe and well tolerated, and it is the only pharmacological therapy approved by the US Food and Drug Administration and the European Medicines Agency for non-24.

Asunto(s)

Benzofuranos/uso terapéutico , Ciclopropanos/uso terapéutico , Receptores de Melatonina/uso terapéutico , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Adolescente , Adulto , Benzofuranos/farmacología , Ciclopropanos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven

RESUMEN

A highly sensitive, specific and rapid liquid chromatography-tandem mass spectrometry technique for the quantification of tasimelteon in human plasma has been developed and validated using tasimelteon-d5 as internal standard. Liquid-liquid extraction technique with ethyl acetate was used for extraction of tasimelteon from the plasma. The chromatographic separation was achieved on an Agilent Zorbax, Eclipse, C18 (4.6 × 50 mm, 5 µm) column using a mobile phase of acetonitrile and 0.02% formic acid buffer (85:15, v/v) with a flow rate of 0.5 mL/min. A detailed method validation was performed as per the United States Food and Drug Administration guidelines. The linear calibration curve was obtained over the concentration range 0.30-299 ng/mL. The API-4000 liquid chromatography-tandem mass spectrometry was operated under multiple reaction monitoring mode during analysis. The validated method was successfully applied to estimate plasma concentration of tasimelteon after oral administration of a single dose of a 20 mg capsule in healthy volunteers under fasting conditions. The maximum concentration of the drug achieved in the plasma was 314 ± 147 ng/mL and the time at which this concentration was attained was 0.54 ± 0.22 h.

Asunto(s)

Benzofuranos/sangre , Benzofuranos/farmacocinética , Cromatografía Liquida/métodos , Ciclopropanos/sangre , Ciclopropanos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Adulto , Benzofuranos/química , Benzofuranos/aislamiento & purificación , Ciclopropanos/química , Ciclopropanos/aislamiento & purificación , Humanos , Límite de Detección , Modelos Lineales , Extracción Líquido-Líquido , Masculino , Reproducibilidad de los Resultados , Adulto Joven

RESUMEN

Two new crystal forms of tasimelteon TSM-I and TSM-II were reported here. Crystallization of crude in methanol or mixture solvent results in anhydrate crystal form (TSM-I) and hemihydrate crystal form (TSM-II) respectively. To the best of our knowledge, it is the first report about crystalline form of tasimelteon. The two crystal forms were exhaustively characterized by Scanning Electron Microscopy, Fourier Transform Infrared Spectroscopy, Raman Spectra, Differential Scanning Calorimetry, Thermogravimetric Analysis, Solid State NMR Spectroscopy and Powder X-ray diffraction and Single Crystal X-ray Diffraction. Furthermore, the pharmacokinetic behavior of TSM-I and TSM-II in rats were measured. We found that though TSM-II is considerably more soluble than TSM-I under water (pH = 7.0) and pH 1.2 buffer conditions, the bioavailability of TSM-Ivia oral administration was better compared to that of TSM-II.

Asunto(s)

Benzofuranos/química , Benzofuranos/farmacocinética , Ciclopropanos/química , Ciclopropanos/farmacocinética , Liberación de Fármacos , Receptores de Melatonina/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría/instrumentación , Rastreo Diferencial de Calorimetría/métodos , Química Farmacéutica/instrumentación , Química Farmacéutica/métodos , Cristalización , Cristalografía por Rayos X/instrumentación , Cristalografía por Rayos X/métodos , Concentración de Iones de Hidrógeno , Masculino , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica de Rastreo , Solubilidad , Espectrofotometría/instrumentación , Espectrofotometría/métodos , Agua/química

RESUMEN

Several aspects of human physiology and behavior are dominated by 24-h circadian rhythms with key impacts on health and well-being. These include mainly the sleep-wake cycle, vigilance and performance patterns, and some hormone secretions. The rhythms are generated spontaneously by an internal "pacemaker," the suprachiasmatic nuclei within the anterior hypothalamus. This master clock has, for most humans, an intrinsic rhythm slightly longer than 24 h. Daily retinal light exposure is necessary for the synchronization of the circadian rhythms with the external 24-h solar environment. This daily synchronization process generally poses no problems for sighted individuals except in the context of jetlag or working night shifts being conditions of circadian desynchrony. However, many blind subjects with no light perception had periodical circadian desynchrony, in the absence of light information to the master clock leading to poor circadian rhythm synchronization. Affected patients experience cyclical or periodic episodes of poor sleep and daytime dysfunction, severely interfering with social, academic, and professional life. The diagnosis of Non-24 Sleep-Wake Rhythm Disorder, also named free-running disorder, non-entrained disorder, or hypernycthemeral syndrome, remains challenging from a clinical point of view due to the cyclical symptoms and should be confirmed by measurements of circadian biomarkers such as urinary melatonin to demonstrate a circadian period outside the normal range. Management includes behavioral modification and melatonin. Tasimelteon, a novel melatonin receptor 1 and 2 agonist, has demonstrated its effectiveness and safety with an evening dose of 20 mg and is currently the only treatment approved by the FDA and the European Medicines Agency.

RESUMEN

INTRODUCTION: Tasimelteon, a novel circadian regulator, is the first product for the treatment of Non-24-hour Sleep-Wake Disorder (Non-24) approved by either the FDA or the European Medicines Agency (EMA). Tasimelteon is a potent and specific melatonin (MT1 and MT2) receptor agonist with 2 - 4 times greater affinity for the MT2 receptor. METHODS: Safety was assessed in two controlled and two open-label studies in blind individuals with Non-24 and in two controlled studies of primary insomnia. Periodic assessments included collection of adverse events (AEs), laboratory testing, electrocardiograms (ECGs), vital sign monitoring, physical examinations and assessment for the potential for suicide. One study included additional assessments for endocrine function. RESULTS: A total of 184 blind individuals with Non-24 received tasimelteon nightly with a median exposure > 1 year. In placebo-controlled studies, 387 patients with insomnia and 42 patients with Non-24 received tasimelteon nightly for 4 - 26 weeks. The total patient years exposure for the six studies assessed here is 258.64 patient years. Discontinuations due to AEs were similar across treatment groups. Overall in the clinical studies described here, AEs attributable to tasimelteon treatment were headache, diarrhea, dry mouth, alanine aminotransferase increased, somnolence, dizziness and nightmare/abnormal dreams. There were no clinically significant differences in treatment group with ECGs, vital signs, withdrawal, endocrine function and suicidality assessments. CONCLUSION: Long-term tasimelteon administration was safe and well-tolerated. This is supported by placebo-controlled data in both Non-24 and insomnia patients.

Asunto(s)

Benzofuranos/efectos adversos , Ciclopropanos/efectos adversos , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Benzofuranos/administración & dosificación , Benzofuranos/farmacología , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacología , Humanos , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Factores de Tiempo

RESUMEN

Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%.

Asunto(s)

Benzofuranos/farmacocinética , Ciclopropanos/farmacocinética , Fluvoxamina/farmacocinética , Cetoconazol/farmacocinética , Receptores de Melatonina/agonistas , Rifampin/farmacocinética , Fumar/efectos adversos , Adolescente , Adulto , Área Bajo la Curva , Benzofuranos/administración & dosificación , Benzofuranos/química , Ciclopropanos/administración & dosificación , Ciclopropanos/química , Inhibidores del Citocromo P-450 CYP1A2/administración & dosificación , Inhibidores del Citocromo P-450 CYP1A2/farmacocinética , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Interacciones Farmacológicas , Femenino , Fluvoxamina/administración & dosificación , Semivida , Humanos , Cetoconazol/administración & dosificación , Masculino , Persona de Mediana Edad , Estructura Molecular , Rifampin/administración & dosificación , Adulto Joven

RESUMEN

Tasimelteon (Hetlioz®), a melatonin receptor agonist, is the first, and, at the time of the publication, the only drug to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of non-24-hour sleep-wake disorder (non-24). This circadian rhythm disorder occurs most commonly in blind individuals without light perception, and it results from their inability to entrain to the 24-hour photoperiod, although the indication does not specify a particular patient population. Non-24 is characterized by a persistent cycle of nighttime insomnia and daytime sleepiness, alternating with asymptomatic periods depending on an individual's degree of circadian rhythm synchronization with the photoperiod at any particular time. Phase II clinical trials in healthy individuals confirmed the circadian phase-shifting potential of tasimelteon. Phase III trials in totally blind subjects diagnosed with non-24 demonstrated the efficacy of tasimelteon in reducing both nighttime wakefulness and daytime napping. Physiologic monitoring revealed that tasimelteon resulted in a higher proportion of individuals becoming entrained to the 24-hour cycle compared with placebo. Safety assessments indicated that tasimelteon is well tolerated, with the most common adverse events being headache, alanine aminotransferase elevation, nightmares or unusual dreams, and upper respiratory or urinary tract infections. Tasimelteon is available as a capsule in a single 20-mg dose and it must be obtained through Vanda Pharmaceutical's HetliozSolutions program with dispensing through a specialty pharmacy. Safety studies in blind individuals diagnosed with non-24 are ongoing and a future clinical trial with Smith-Magenis syndrome patients is planned.

Asunto(s)

Ciclos de Actividad/efectos de los fármacos , Benzofuranos/uso terapéutico , Ceguera/complicaciones , Ciclopropanos/uso terapéutico , Receptores de Melatonina/agonistas , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Animales , Benzofuranos/efectos adversos , Benzofuranos/farmacocinética , Ciclopropanos/efectos adversos , Ciclopropanos/farmacocinética , Interacciones Farmacológicas , Humanos , Receptores de Melatonina/metabolismo , Transducción de Señal/efectos de los fármacos , Sueño/efectos de los fármacos , Trastornos del Sueño del Ritmo Circadiano/etiología , Trastornos del Sueño del Ritmo Circadiano/metabolismo , Trastornos del Sueño del Ritmo Circadiano/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Vigilia/efectos de los fármacos

RESUMEN

INTRODUCTION: Melatonin is a neurohormone involved in the regulation of circadian rhythms, with potent antioxidant activity. It has a wide functional repertoire, with effects almost on all tissues and organs. It is mainly used as a dietary supplement for sleep regulation and re-synchronization of disrupted circadian rhythms. Melatonin has very low toxicity, but some pharmacokinetic issues, such as limited oral bioavailability and short half-life, limit its tissue availability. AREAS COVERED: Patents and patent applications from 2012 to September 2014 in which melatonin or synthetic analogues are claimed for the prevention or treatment of pathological conditions. EXPERT OPINION: Melatonin is considered a valuable substance that can be safely administered for the prevention and treatment of many diverse diseases. A major trend in 2012 - 2014 patents is the co-administration of melatonin with other drugs to increase the efficacy of the treatment and reduce side-effects. Two different actions have been combined in hybrid ligands (e.g., melatonin-tamoxifen and melatonin-tacrine derivatives). Further experimental evidence is needed to support the usefulness of these approaches. The number of new melatonin analogues has shown a marked decrease in the past 3 years, with claimed applications mainly as hypnotic or antioxidant agents.

Asunto(s)

Antioxidantes/uso terapéutico , Ritmo Circadiano/fisiología , Melatonina/uso terapéutico , Animales , Antioxidantes/farmacocinética , Disponibilidad Biológica , Suplementos Dietéticos , Semivida , Humanos , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/uso terapéutico , Ligandos , Melatonina/metabolismo , Melatonina/farmacocinética , Patentes como Asunto , Distribución Tisular

RESUMEN

Hetlioz(®) (tasimelteon) is the first approved treatment in the United States for Non-24-Hour Sleep-Wake Disorder (Non-24). We present here data on the in vitro binding affinity of tasimelteon for both human melatonin receptors MT1 and MT2, as well as the extended screen of other receptors and enzymes. Results indicate that tasimelteon is a potent Dual Melatonin Receptor Agonist (DMRA) with 2.1-4.4 times greater affinity for the MT2 receptor believed to mediate circadian rhythm phase-shifting (Ki = 0.0692 nM and Ki = 0.17 nM in NIH-3T3 and CHO-K1 cells, respectively), than for the MT1 receptor (Ki = 0.304 nM and Ki = 0.35 nM, respectively). Tasimelteon was also shown to have no appreciable affinity for more than 160 other pharmacologically relevant receptors and several enzymes.

Asunto(s)

Benzofuranos/metabolismo , Ciclopropanos/metabolismo , Receptores de Melatonina/agonistas , Receptores de Melatonina/metabolismo , Benzofuranos/química , Ciclopropanos/química , Humanos , Unión Proteica